To evaluate the presence and progression of radiographic joint damage, as assessed with the adapted Sharp/van der Heijde score (SHS), in individual joints in the hand and wrist in patients with juvenile idiopathic arthritis (JIA) and to compare progression of damage among different JIA categories.
A total of 372 radiographs of both wrists and hands obtained at first observation and at last followup visit (after 1–10 years) in 186 children with polyarticular-course JIA were evaluated. All radiographs were scored using the adapted SHS by 2 independent readers. Radiographic assessment included evaluation of joint space narrowing (JSN) and erosions on baseline and last followup radiographs and of progression of radiographic changes from baseline to last followup radiographs.
Both JSN and erosions occurred in all adapted SHS areas. Overall, radiographic damage and progression were more common in the wrist and less common in metacarpophalangeal (MCP) joints. The hamate and capitate areas appeared particularly vulnerable to cartilage loss. Erosions were identified most frequently in the hamate and capitate bones as well as in the second and third metacarpal bases. Patients with extended oligoarthritis were distinctly less susceptible to JSN in hand joints, whereas patients with polyarthritis showed a greater tendency to developing erosions in hand joints.
Radiographic joint damage and progression in our patients with JIA were seen most commonly in the wrist and less commonly in MCP joints. The frequency and localization of structural abnormalities differed markedly across disease categories.
Juvenile idiopathic arthritis (JIA) is a chronic and heterogeneous disease characterized by prolonged synovial inflammation that may lead to permanent damage of the articular cartilage and bone (). Because the prevention of irreversible joint changes is a key objective in the long-term management of chronic arthritis, evaluation of radiographic joint damage represents an important clinical tool for assessing disease severity and progression and for monitoring the effectiveness of therapeutic interventions. Although newer imaging techniques such as magnetic resonance imaging (MRI) and ultrasound allow earlier detection of bone and cartilage changes, conventional radiography remains the gold standard for the demonstration of structural joint lesions in patients with JIA ().
Several studies have shown that many children with JIA experience significant radiographic joint damage ([3-8]) and that a sizeable percentage of them develop cartilage loss and erosions early in their illness ([7-9]). However, the experience with the use of quantitative scoring systems in childhood arthritis is still limited. In recent years there has been a great deal of effort aimed to devise and validate radiographic scoring methods for use in JIA ([3, 4, 10-18]). These studies have shown that structural joint changes can be assessed reliably in children with arthritis. The advances in radiographic scoring suggest that the time has come to include quantitative measures of radiographic damage in therapeutic trials in JIA ().
Among the existing pediatric scoring systems, the adapted Sharp/van der Heijde score (SHS) is regarded as the most comprehensive and reliable, as it has shown the best properties in terms of reproducibility, construct validity, and capability to detect radiographic progression over time (). However, this method requires the assessment of joint space narrowing (JSN) and erosion in many areas in both hands and wrists ([18, 20]). Therefore, it is complex and time consuming, particularly in the case of significant damage or a high level of progression.
It has been suggested that time to score and disagreement among independent readers in radiographic scoring could be decreased by deleting those joints that contribute less to damage or progression, or those individual domains of JSN or erosions that are less frequently affected (). Importantly, mapping the prevalence and location of structural abnormalities in different sites on conventional radiology may provide useful information to guide future investigations with MRI and ultrasound.
The primary aim of the present study was to evaluate the frequency of both involvement and progression of radiographic damage, as assessed with the adapted SHS, in individual joints in the hand and wrist in children with JIA. A secondary aim was to compare radiographic progression in individual joints among different disease categories of JIA.
Box 1. Significance & Innovations
This study provides information on the frequency and distribution of radiographic joint damage in juvenile idiopathic arthritis.
Radiographic damage was overall more common in the wrist and less common in metacarpophalangeal joints.
There were remarkable differences in the frequency of location of structural joint changes among different disease categories.
The study findings provide useful information to guide future investigations with magnetic resonance imaging and ultrasound.
PATIENTS AND METHODS
Study design and selection of patient radiographs
The study radiographs were part of a sample of 587 films of both wrists and hands in the posteroanterior view obtained from January 1986 to December 2004 in 186 children with polyarticular-course JIA () and hand and/or wrist joint involvement. The radiographs of 177 of the 186 study patients were used in a previous analysis aimed to validate the adapted pediatric version of the SHS scoring system (). The radiographs of the 9 patients not included in the previous study were scored, together with the radiographs of the 177 patients included, by the same readers using the same method. However, those radiographs were not included in that study because they were evaluated in the context of the training session that preceded the formal study. For the purposes of the present study, only the radiographs obtained at baseline (first observation) and at last followup visit (after 1–10 years) were retained. None of the radiographs were rescored for the current analysis, but the radiographic scores obtained in the previous study were reanalyzed with a special focus on the research question. The study protocol was approved by the Independent Ethics Committee of the Istituto Giannina Gaslini of Genova, Italy.
All radiographs were scored using the SHS ([18, 20]). In brief, this method applies to 15 areas for JSN and 21 areas for erosion or bone deformity in each hand and wrist. Bone deformity is considered equivalent to bone erosion because in younger children with chronic arthritis radiographic damage frequently manifests in carpal bones, and to a lesser extent in distal metacarpal epiphyses, owing to the unique phenomenon of disturbance of bone growth, as deformity in shape, from squaring to squeezing to gross deformity, rather than as discrete erosion (). Scores for JSN and erosion in each area range from 0–4 and from 0–5, respectively. The total SHS score is calculated as the sum of the scores for JSN (range 0–120) and erosion (range 0–210) and ranges from 0–330. To facilitate assignment of SHS scores, each patient's radiograph was compared with a wrist/hand radiograph from a healthy child with the same bone age. The SHS scores were assigned to all study radiographs by 2 independent readers (XN and MI). Radiographs from each patient were read in sequential order and previous radiographs and scores were available to observers when examining and scoring followup radiographs. The readers had no information on International League of Associations for Rheumatology (ILAR) categories, disease duration and disease activity, or severity. Both inter- and intraobserver reliability were good (). The average score determined by the 2 readers for each radiograph was used for the analyses. The areas included in the SHS score are shown in Figure 1. An example of scoring of JSN and erosion/bone growth disturbance in a growing child is provided in Figure 2.
Radiographic assessment included evaluation of the amount of radiographic damage on baseline and last followup radiographs and of the progression of radiographic damage from baseline to last followup radiographs. Both radiographic damage and progression were evaluated separately for JSN and erosion and were assessed in each hand and wrist area included in the SHS. Radiographic damage was defined as a score >0 for both JSN and erosion. Radiographic progression was determined by calculating the change in the JSN and erosion score between the radiographs obtained at baseline and those obtained at last followup visit. A negative value indicated radiographic progression, whereas a value of 0 or a positive value indicated no progression. Because preliminary analyses did not show substantial differences in radiographic damage and progression between right and left hands and wrists, the right and left sides were considered together, i.e., an area was considered abnormal when at least 1 side was abnormal. We anticipated that an individual area could be considered for removal from the scoring system when it was involved in <5% of patients.
The percentage of patients with radiographic damage or progression by JSN or erosions per area was extracted from the study database. In order to visualize radiographic abnormalities on a per-area basis, data were presented as percentage of patients with involvement (95% confidence interval [95% CI]) or by plotting histograms. The histograms express all individual areas on the x-axis and the percentage of patients with involvement on the y-axis.
To gain insight into the relative erosive potential of different JIA subsets, radiographic progression was compared among patients belonging to the ILAR categories more represented in the study patients (systemic arthritis, polyarthritis, and extended oligoarthritis). Furthermore, to examine whether children with early disease had a distinctive pattern of radiographic progression, a sensitivity analysis was made to compare the findings obtained in the entire patient sample with those seen in a subset of 130 patients who had the baseline radiograph taken within 2 years after disease onset. In addition, the amount of radiographic progression in the whole followup period in the entire patient sample was compared with that observed between baseline and 1 year in the 152 patients who had the 1-year radiograph available.
Of the 186 patients whose radiographs were evaluated in the study (58 boys, 128 girls), 45 had systemic arthritis, 52 had polyarthritis (7 were rheumatoid factor [RF] positive), 53 had extended oligoarthritis, 10 had psoriatic arthritis, and 26 had undifferentiated arthritis. The mean age at disease onset was 4.2 years (range 0.3–15.7 years), and the mean disease duration at baseline was 1.6 years (range 0.2–7.1 years). The study radiographs were taken from January 1986 to December 2004. During the study period, 179 patients (96%) had received methotrexate, 27 patients (14.7%) had received biologic medications, and 100 patients (54%) had received systemic corticosteroids. The time interval between baseline and last followup radiograph was 1 year in 56 (30%) patients, 3 years in 41 (22%) patients, 5 years in 40 (21.5%) patients, 7/8 years in 30 (16.1%) patients, and 10 years in 19 (10.2%) patients. A total of 372 radiographs (186 obtained at baseline and 186 at last followup visit) were available for study.
Table 1 shows the percentage (95% CI) of patients who had JSN in hand and wrist areas at baseline and last followup visits, as well as the frequency of progression of JSN in individual areas. In general, wrist areas were more frequently involved than hand areas, and proximal interphalangeal (PIP) areas were more frequently affected than metacarpophalangeal (MCP) areas. Damage was most common in the hamate and capitate areas of the wrist. Among PIP areas, cartilage loss was detected most frequently in the fourth and fifth joints. The fourth joint was the least commonly affected of MCP areas. Overall, the relative frequency of JSN was similar at baseline and at last followup evaluations across areas, although wrist areas, and to a lesser extent MCP areas, revealed a tendency to develop more damage over time than PIP areas.
Table 1. Frequency of presence and progression of joint space narrowing on a per-area level*
Values are the percentage (95% confidence interval). PIP = proximal interphalangeal; MCP = metacarpophalangeal; CMC = carpometacarpal.
aFrom baseline to last observation.
In general, changes (i.e., progression) in JSN score paralleled the pattern of involvement at initial and final cross-sectional evaluations, with the areas preferentially affected showing the greatest tendency to worsen over time. However, JSN progression in MCP and PIP areas was similar overall. The hamate and capitate areas appeared to be distinctly more vulnerable to cartilage loss. All areas were involved in >5% of patients. Sensitivity analyses of progression of JSN in the whole followup period in the 130 patients with disease duration <2 years at baseline and in the first year of followup in the 152 patients who had a 1-year radiograph available did not show appreciable differences in the distribution of damage with what was found in the entire patient sample (results not shown).
Table 2 illustrates the frequency of erosion in hand and wrist areas at baseline and last followup visits, as well as the frequency of progression of erosion in individual areas. As seen for JSN, wrist areas were more frequently involved than hand areas, and PIP areas were more frequently affected than MCP areas. The difference between wrist and hand areas became more evident at last followup observation, particularly for MCP areas. Overall, the predominance of damage in PIP over MCP areas was more evident for erosion than for JSN. Damage was most common in the capitate and third carpometacarpal joint of the wrist. Among PIP areas, damage was detected most frequently in the second, third, and fourth joints. The fifth joint was the most commonly affected MCP area. Involvement of the radial area was more frequent than that of the ulnar area. Overall, the relative frequency of erosion was similar at initial and final evaluations across areas, although wrist areas, and to a lesser extent MCP areas, revealed a tendency to develop more damage than PIP areas.
Table 2. Frequency of presence and progression of erosion on a per-area level*
As seen for JSN, changes (i.e., progression) in erosion score paralleled the pattern of involvement at baseline and last followup visits, with the areas preferentially affected showing the highest tendency to worsen over time. Importantly, 4 of the 5 wrist areas added to the original SHS score showed the greatest potential for progression of erosion damage, which supports their inclusion in the pediatric adaptation of the score. All areas were involved in >5% of patients. A sensitivity analysis of progression of erosion in the whole followup period in the 130 patients with disease duration <2 years at baseline and in the first year of followup in the 152 patients who had a 1-year radiograph available did not show appreciable differences in the distribution of damage with what was found in the entire patient sample (results not shown).
Figures 3 and 4 depict the frequency of progression of JSN and erosion scores, respectively, in individual areas in patients divided by ILAR category. In general, progression of both JSN and erosion scores in PIP and MCP areas was less common in patients with extended oligoarthritis than in children with systemic arthritis and polyarthritis. Patients with extended oligoarthritis also had lesser progression of wrist erosions, whereas progression of JSN in wrist areas in children with this disease category was close to that seen in patients with systemic arthritis and polyarthritis. Patients with polyarthritis showed the greatest frequency of erosion progression in both PIP and MCP areas. Patients with systemic arthritis had the greatest frequency of progression of both JSN and erosion in the hamate areas, whereas JSN progression in the capitate was most common in patients with polyarthritis. The frequency of erosion score progression in children with extended oligoarthritis was <5% in all MCP areas, except for the fifth MCP joint, and in the first PIP joint and first carpometacarpal joint. The disease duration at baseline visit as well as the interval between first and last radiographs was comparable across the 3 disease categories (data not shown).
Our study is the first to investigate the frequency and distribution of radiographic joint damage in JIA. The patient population was composed of children with polyarticular-course disease and involvement of hand and/or wrist joints. Radiographic changes are known to occur most frequently in patients with polyarticular-course JIA ([5, 23, 24]). Several lines of evidence indicate that the wrist, together with the hip, is a vulnerable site of radiographic changes in patients with JIA ([9, 23, 25]). Wrist disease has been associated with a more severe course of arthritis ([26, 27]), a poorer functional outcome (), and a lesser likelihood of response to methotrexate and of remission under etanercept therapy ([28, 29]). In a recent clinical trial of methotrexate in children with polyarthritis, involvement of the wrist and/or hand joints was present at baseline in 85% of the patients ([18, 30]). Thus, the wrist and hand joints are suitable sites to investigate radiographic damage and its progression in patients with polyarticular JIA.
We found that both JSN and erosions occur in all areas that are included in the SHS. Although involvement and change in both score components were most prevalent in the wrist, radiographic damage was detected in PIP and MCP joints in a sizeable proportion of patients. This finding indicates that all joints contributed in determining the score and its change over time. It has been suggested that owing to the greater potency of the modern antiarthritis medications, which have led to a generalized reduction in progression rate, there is the need to use sufficiently comprehensive radiographic scores in future clinical trials to overcome the greater challenges posed to the scoring methods in terms of discriminative power between index and comparator agents ().
In our patients, radiographic damage affected preferentially certain sites. The hamate and capitate areas appeared particularly vulnerable to cartilage loss. Erosions were identified most commonly in the hamate and capitate bones, as well as in the second and third metacarpal bases. Notably, these bones have been found to be among the most frequent locations of MRI-detected erosions (). Altogether, these observations suggest that the central part of the wrist is distinctly susceptible to the erosive process in patients with JIA. That the 5 new wrist areas included in the pediatric adaptation of the SHS were among the most commonly affected erosion sites supports their addition to the original version of the score. In the hands, radiographic changes, particularly erosions, were overall more frequent in PIP joints than in MCP joints. This finding contrasts with what is seen in adult patients with rheumatoid arthritis, where involvement of MCP joints predominates (). Recently, Elhai et al found that radiographic damage was more common in MCP joints than in PIP joints in children with polyarticular JIA persisting into adulthood (). The disparity between our findings and those of Elhai et al may depend, at least in part, on differences in the characteristic of the study population. In particular, the frequency of RF positivity, which identifies a category of JIA that is considered the pediatric equivalent of adult RF-positive rheumatoid arthritis (), was 54% in the sample of Elhai et al () and only 3.8% in our cohort.
The comparison of progression rates among ILAR categories showed some peculiar patterns. Patients with extended oligoarthritis were distinctly less susceptible to JSN in hand joints than patients with polyarthritis and systemic arthritis. The same disparity was seen for erosion in the MCP joints, though not in the PIP joints (with the exception of the first ray). These findings indicate that hand joints are less relevant than wrist joints for the assessment of radiographic damage in this patient subset. This phenomenon could be due to the tendency of children with extended oligoarthritis to develop a scattered and asymmetric involvement of hand joints, rather than the symmetric pattern that is often seen in patients with polyarthritis and systemic arthritis. Patients with extended oligoarthritis also had fewer wrist erosions than did patients with the other disease categories, whereas the susceptibility to JSN in the wrist was comparable across subtypes.
Patients with polyarthritis showed a greater propensity to developing erosions in hand joints than patients with systemic arthritis, whereas the potential for JSN was comparable in all sites between patients with polyarthritis and systemic arthritis. However, patients with systemic arthritis had a distinctly greater risk of developing both JSN and erosion in the hamate areas, whereas JSN around the capitate was most prevalent in patients with polyarthritis.
Our study should be interpreted in the light of certain limitations. Radiographs were not blind for chronological sequence. There is no definite consensus regarding whether readers should be aware of the time order of radiographs (). Notably, blinding of films to chronological order in children is impossible due to readily apparent growth and maturation of the skeleton. The study radiographs were obtained in standard clinical care and not in the context of a randomized trial. This makes it impossible to establish whether radiographic progression was influenced by specific therapies. Only a small proportion of patients were treated with biologic medications, which may be more effective than traditional disease-modifying drugs in reducing radiographic progression in JIA (). Thus, the amount of radiographic damage observed in our study may be greater than that seen currently in consequence of the widespread use of biologic medications. Nevertheless, the information gained in our study provides a benchmark for future comparisons in the biologic medications era. Although we found evidence that all bone and joint areas contributed to determine the score (with the possible exception of some erosion areas in the extended oligoarthritis subset), we did not investigate whether the removal of particular joints would influence the performance of the score in terms of responsiveness to change and discriminative capacity. We acknowledge that because the scoring system used in the study assesses radiographic damage only in the wrist/hand joints, our findings are of value only for patients with involvement of these joints.
In summary, we have shown that radiographic joint damage and progression in children with JIA occurs most commonly in the wrist and less commonly in MCP joints. However, all areas included in the adapted SHS contributed to some extent in quantifying radiographic changes and their progression over time. There were noticeable disparities in the frequency and localization of structural abnormalities among different disease categories.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Ravelli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Giancane, Pederzoli, Ruperto, Martini, Ravelli.
Acquisition of data. Giancane, Pederzoli, Norambuena, Ioseliani, Sato, Gallo, Negro.
Analysis and interpretation of data. Giancane, Pistorio, Martini, Ravelli.