Juvenile idiopathic arthritis (JIA) is the most frequently occurring inflammatory rheumatic condition in childhood, with an annual incidence of 10–20 cases per 100,000 children and an estimated prevalence of 90–130 cases per 100,000 children (1–4). The term JIA refers to a heterogeneous group of patients with different characteristics, outcomes, extraarticular manifestations, serologic findings, and genetic markers (5–7). Juvenile rheumatoid arthritis (JRA) and juvenile spondylarthropathy are the 2 major subcategories of JIA. Sacroiliitis is considered to be the gold standard for a diagnosis of spondylarthropathy and is characterized by clinical and radiographic signs of arthritis in the sacroiliac joints (8–10). However, many years may elapse between the time of onset of arthritis and the onset of axial involvement in children, and identification of sacroiliitis in patients with JIA requires long-term followup.
The annual incidence of juvenile spondylarthropathies is 1–69 per 100,000 children (1). The wide variation in reported frequency may be partly attributable to differences in the classification of patients. Criteria for the classification of ankylosing spondylitis (AS) in adults have been used to classify juvenile AS in persons in whom symptoms develop before age 16 years (10). However, the frequency of peripheral arthritis is higher, and symptoms and signs of spinal and sacroiliac involvement are fewer in patients with juvenile-onset AS than in those with adult-onset AS (8, 11).
Criteria have been developed to identify conditions related to juvenile AS, such as juvenile psoriatic arthritis (PsA), syndrome of seronegative enthesopathy and arthropathy (SEA), and enthesitis-related arthritis (12–14). Nonetheless, early manifestations of an evolving spondylarthropathy may be incorrectly classified as JRA (8, 15). Furthermore, accurate classification of childhood arthritides depends on the identification of clusters of characteristics, clinical features, and laboratory findings. Identification of clinical features (e.g., numbers of affected joints and the presence of enthesitis) is subjective and varies between raters (16). Therefore, use of objective measures such as radiographs and immunogenetic markers is recommended for the evaluation of classification criteria and the identification of homogeneous subtypes of JIA (17).
Radiographic assessments of sacroiliac joints have been performed in patients with selected subtypes of JIA (8, 9, 18, 19). To our knowledge, the frequency of radiographic sacroiliitis in JIA in general has not yet been assessed.
Juvenile-onset AS, like adult-onset AS, is strongly associated with the presence of HLA–B27. Furthermore, an increased prevalence of HLA-DRB1*08 in Norwegian and Mexican juvenile AS patients has been reported (20, 21), indicating that HLA-encoded genes other than B27 may also contribute to the development of sacroiliitis in children.
Male sex, disease onset in late childhood, pauciarticular subtype, enthesitis, and a family history of related disease all have been associated with juvenile spondylarthropathy (5, 13, 22, 23). However, the relative importance of patient characteristics, genetic markers, and early disease variables in the development of sacroiliitis has not yet been assessed.
Two previous studies compared the disease course in children with juvenile spondylarthropathies with that in children with JRA (5, 23). The results demonstrated differences between the 2 subgroups in joint patterns and the frequency of axial signs and symptoms. Data on the long-term outcome of patients with juvenile spondylarthropathy are scarce (18).
In the current study, we used radiographically evident sacroiliitis as an objective measure of long-term outcome in a cohort of patients with JIA who were followed up for a median of 14.9 years after disease onset. It was estimated that during this period, ∼70% of the Norwegian children with diagnosed JIA were admitted to the hospital (24). The aim of our study was to assess the frequency of sacroiliitis in JIA and to determine the role of genetic markers, patient characteristics, and early-disease variables in the development of sacroiliitis. We also sought to describe the clinical and radiographic outcome in JIA patients with and those without sacroiliitis.
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- PATIENTS AND METHODS
In the present study, the frequency of radiographic sacroiliitis in JIA was 6% after a median disease duration of 14.9 years. This frequency is higher than the 2% prevalence of juvenile AS reported in most pediatric rheumatology registers (36–39). The long duration of followup may have increased the frequency of sacroiliitis in our cohort. Furthermore, when radiographs of all JIA patients were obtained, sacroiliitis was seen almost twice as frequently as in clinical practice. Our results are consistent with the high frequency of sacroiliitis (9–92%) seen in radiographic assessments of patients with various subtypes of JIA (8, 9, 18, 19, 40).
DP2 was an independent protective factor, and HLA–B27, early hip joint involvement, and disease onset after age 8 years were risk factors for development of sacroiliitis. DP2 was statistically significantly decreased in patients with sacroiliitis and pauciarticular-onset JIA but not in those with sacroiliitis and polyarticular arthritis. This result is consistent with the fact that DP2 is a well-known correlate of pauciarticular-onset JRA (7, 20, 41, 42). The identification of HLA–B27 as a predictor of sacroiliitis is in accordance with the strong associations between HLA–B27 and juvenile AS demonstrated in several previous studies (5, 9, 43, 44). Hip joint involvement during the first 6 months of disease was an important correlate of sacroiliitis in our study. An association between hip involvement and juvenile AS has been reported by other investigators (5, 23). Several studies have shown that late onset is associated with the development of juvenile spondylarthropathy, supporting our suggestion that age at disease onset influences the risk for sacroiliitis (18, 22, 23, 45). However, the reliability of the predictive factors identified here may be influenced by the limited number of patients with sacroiliitis.
Enthesitis, male sex, and axial symptoms at onset were associated with the development of sacroiliitis but were not identified as predictors in the present study. An association between these factors and the development of juvenile AS has been found in numerous previous studies (5, 18, 22, 23, 45). Information about the prevalence of sacroiliitis in juvenile PsA is scarce. We found that sacroiliitis developed in 3 of 10 patients who had psoriasis at disease onset. Further studies are needed to determine whether axial involvement is more frequent in juvenile PsA than in other subgroups of JIA.
In our study, the frequency of DR4 was higher in patients with sacroiliitis than in either patients without sacroiliitis or healthy controls. All but 1 of the patients with sacroiliitis had peripheral arthritis. A German study previously demonstrated that DR4 was associated with adult AS complicated by peripheral arthritis (46), but this association was not seen in a Finnish patient population (47). Ploski et al reported a weak but nonsignificant increase in DR4 in patients with juvenile AS (20). The selection of patients may explain the difference in these results. An increased frequency of DR4 has consistently been seen in patients with RF-positive, late-onset polyarticular JRA (48, 49). In our study, 1 of the patients with sacroiliitis and DR4 had IgM-RF–positive, late-onset polyarticular JRA, and the possibility that this patient might have 2 conditions cannot be excluded.
In adult RA, DR4 has been associated with radiographic progression (50), and Burgos-Vargas et al suggested that sacroiliitis was a marker of severe arthritis in patients with SEA (5). The association between DR4 and sacroiliitis in our cohort might support the hypothesis that DR4 is a marker of disease severity in children with juvenile spondylarthropathy and peripheral arthritis. In the present multivariate analysis, however, DR4 was not significantly correlated with the development of sacroiliitis, showing that this factor was not an independent predictor of sacroiliitis. HLA–DR8 was associated with JIA in patients both with and without sacroiliitis in our study, as has previously been demonstrated (20, 21).
Stereoscopic examination of the sacroiliac joints in the anteroposterior view is regarded as a good, conventional approach to investigating these joints, because it provides a combination of sharp outlines and 3-dimensional views (51, 52). Conventional radiographs may be less sensitive than contrast-enhanced magnetic resonance imaging and computed tomography for the early detection of sacroiliitis (19, 53). It remains to be shown whether such early changes predict a later transition to juvenile AS (10, 19, 53). In the present study, the radiographs were evaluated by 2 independent radiologists who have worked with rheumatic diseases for many years.
Sixty-five percent of our patients with radiographic sacroiliitis had inflammatory back pain, and spinal mobility was reduced in 75% after a median disease duration of 14.9 years. The lack of Norwegian controls limited evaluation of these results. However, signs and symptoms of axial involvement were more frequent in JIA patients with sacroiliitis than in those without sacroiliitis, and our results are in accordance with those of previous studies indicating that spinal involvement is a frequent outcome of juvenile spondylarthropathy (5).
In our study, the frequency of erosions of any peripheral joint was higher in patients with sacroiliitis than in those without sacroiliitis. The reliability of this finding is influenced by the fact that radiographs of affected peripheral joints other than hips, ankles, and tarsi were obtained only when clinically indicated and were not obtained for all patients and examined in a blinded manner. Consistent with previous results, radiographic changes of the hips and the calcanei were associated with sacroiliitis (5, 11, 22, 45, 54–56).
The participants in the present study represented all new patients with JIA who were admitted to the hospital between 1980 and 1985. Patients who are admitted to hospitals tend to have more severe disease than those who are recruited from the general population. However, the public health care system in Scandinavia, which provides regular free checkups for all children of preschool and school age, probably facilitates admission of most children with chronic rheumatic diseases (4). The age, sex, and disease onset type of the present cohort of JIA patients were similar to those of patients in previous epidemiologic studies (3, 4, 57, 58), indicating that the participants were relatively representative of patients with diagnosed JIA.
In our patients, the most frequent type of onset of arthritis was pauciarticular, in those both with and without sacroiliitis, as previously demonstrated among patients with juvenile spondylarthropathy and JRA (1, 4, 5, 11, 22, 45). In contrast with the results of Burgos-Vargas et al, the pauciarticular:polyarticular ratio did not tend to be higher in patients with sacroiliitis than in those without sacroiliitis (5). Our results support the contention that, although prevalent, pauciarticular onset is not an important discriminator between juvenile spondylarthropathy and other childhood arthritides (5). However, retrospective assessment of the early disease variables may have influenced the reliability of our data concerning disease onset.
In the present long-term followup study, the prevalence of radiographic sacroiliitis in JIA was 6%. Spinal mobility was reduced in most patients with sacroiliitis. Our results indicate that, in addition to HLA–B27, DP2 can contribute to the early differentiation of juvenile spondylarthropathy from other arthritides. Furthermore, early hip involvement and late onset were related to the progression of sacroiliitis in JIA. We look forward to future studies for a determination of the reliability of early predictors of sacroiliitis in children.