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- PATIENTS AND METHODS
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease of the spine that affects 0.2–0.8% of the population (1). Although AS typically presents in the late teens or early twenties, it can present in childhood. When symptom onset occurs in individuals <16 years of age and individuals go on to develop radiographic sacroiliitis at a later stage, the disease is termed juvenile-onset AS (JoAS) (2). Among patients with AS, prevalence rates for juvenile onset vary from 9% to 21% in white populations, although prevalence rates ≥40% have been reported with Mexican Mestizo and Korean AS patients (3).
Although adult-onset AS (AoAS) and JoAS share many common features, both being characterized by the presence of radiographic sacroiliitis, they also differ in many respects. JoAS presents more commonly with peripheral joint symptoms and adults are more likely to present with axial manifestations. Differences in functional outcome have also been reported that depend on the age of onset. In a study comparing 24 JoAS with 71 AoAS patients, JoAS had worse functional outcome (4). In another study comparing functional outcome in 22 JoAS with 22 AoAS patients, no difference was observed (5). There are several reasons for the discrepancies reported between the studies, such as small sample size and the lack of a common definition of outcomes, making direct comparison between studies difficult. In addition, several phenotypic manifestations of JoAS exist that may account for differences in determining functional outcomes. Burgos-Vargas et al described a characteristic group of JoAS patients with “genuine adult-like AS” as opposed to patients who present with the syndrome of enthesopathic arthritis and evolve subsequently into AS (3).
No comparison of functional outcome of JoAS with AoAS has been performed to date in a North American cohort. The potential for biologic agents to improve functional outcome in AS has recently been demonstrated in several short-term randomized controlled trials (6–8). For this reason and because functional outcome has been shown to be the most important predictor of total costs in AS (9), it is important to determine why some patients have a poor functional outcome. The objective of this study was to compare functional outcome of JoAS with AoAS and to identify predictors of a poor functional outcome of JoAS.
- Top of page
- PATIENTS AND METHODS
This is the first North American study of AS patients that attempts to compare functional outcome in JoAS patients with that in AoAS patients, and is the largest published series to do so. In this study, we found that JoAS patients experience a greater delay in diagnosis compared with AoAS patients and suffered more functional impairment compared with AoAS patients with the latter holding even when controlled for disease duration. Women with JoAS appear to develop functional impairment earlier than men with JoAS. Multivariate analysis demonstrated that age and low income status were strongly associated with worse functional outcome in JoAS compared with AoAS.
One strength of this study lies in the large number of JoAS patients (n = 326) who participated in the survey, the largest reported in the literature to date. Because this survey targeted patients in the population, it is likely that this cohort represents a spectrum of AS disease severity compared with patients recruited only from a tertiary referral center. A unique aspect of the study was that there was representation from all states in the US, although the greatest numbers came from California and New York. Despite the large number of respondents, it is acknowledged that the overall response rate to the survey was 30%. This may be due to the fact that a large number of patients who were mailed questionnaires from the SAA database were those who had only made an inquiry to the SAA. On the other hand, the response rate from current members of the SAA was high, at 78%. It is possible that nonresponders included a high percentage of patients who in fact had never been diagnosed with AS, particularly since the response rate for SAA inquiries was only 19%.
The large sample size facilitated a multivariate analysis to identify factors associated with outcome in JoAS. This was not possible in previous studies because of smaller sample sizes (4, 5). However, a limitation of a cross-sectional study design is that it precludes drawing any definitive conclusion about prognostic indicators of outcome. Therefore we were only able to identify strongly associated variables that may be predictors of outcome. A prospective observational cohort study with patients enrolled at inception would be required to confirm if the identified variables are true predictors of outcome. To date, a large epidemiologic cohort of AS patients has not been compiled in North America. The low incidence of the disease and the prolonged delay in diagnosis pose logistic problems for conducting such a study.
In this study, the diagnosis of AS was made by self report and this does have limitations with regard to misclassification of cases. It is possible that this would bias the results by including some patients who did not have the disease. The bias would, however, most likely be the same for JoAS and AoAS. We did ask patients which health professional made the diagnosis and there was no difference between groups. Almost 90% of individuals reported that the diagnosis was made by a physician. In addition, there were no differences between the 2 groups and the validation cohort where the diagnosis was confirmed by a physician. This was the reason we decided a validation cohort was important to include in the study design.
We acknowledge that questioning patients about symptom onset may be fraught by recall bias. However we feel that the recall bias in this instance may have lead to an underestimation of the true disease duration for many AS patients. Patients are more likely to remember episodes of disease activity and forget good periods. Therefore we may have biased the results toward underestimation of disease duration or indeed delay in diagnosis. Prospective followup of patients from date of onset of symptoms is the only means of avoiding recall bias.
No recent studies have been performed comparing JoAS to AoAS. The existing publications are older studies, each reporting on a small number of patients. The management of AS has changed markedly in recent years, with biologic therapies increasingly prescribed for many patients, which makes comparison of patient outcomes between our study and these older studies difficult. In addition, several methodologic differences further limit direct comparisons between studies.
In one study, a survey was conducted of 3,000 AS patients of whom 135 had JoAS (11). The results were compared with 135 respondents who had AoAS. Functional impairment was measured using the Arthritis Impact Measurement Score (AIMS) (12), which may not be as sensitive as the BASFI for detecting disease-specific functional impairment in AS. The authors reported that functional impairment, disability, and impact of disease were less marked in JoAS compared with AoAS. However, the JoAS patients had a mean age of 37.3 years at the time of sampling compared with our cohort, which had a mean age of 46.5 years at time of survey. In our study, age was identified as being significantly associated with functional outcome. Therefore, this difference in age at the time of sampling between studies may account for the discrepancy in reported outcomes between studies.
In another study by the same group, 22 JoAS patients were compared with 22 AoAS patients (5). There were some similarities with our study; delay in diagnosis was greater in JoAS compared with AoAS, with women experiencing the longest delay in diagnosis. Patient numbers did not allow an analysis stratified by sex or a multivariate analysis. The results of this study may have been limited by referral bias, as patients with milder disease may not have been included because this study was based on patients recruited from a tertiary referral center.
Garcia-Morteo et al (4) addressed the comparison of the 2 clinical entities in a retrospective study. The authors concluded that functional impairment was more severe in the JoAS group. Nineteen percent (n = 24) of the patients in this study had JoAS, as compared with 14% of our cohort. Seventy-one patients with AoAS were included in the study. Of these, only 46 patients were evaluated for functional outcome. In the study, all 24 patients with JoAS exhibited some degree of functional impairment, as defined by the American College of Rheumatology functional classification system, after mean disease duration of 15 years. In comparison, 80% of patients with AoAS were classified as having functional impairment. The methodology of the study was not adequately outlined to determine why the remaining individuals were not reported on for this outcome.
Our study had some important messages for clinicians. There persists a significant delay in diagnosis that is more marked for JoAS than AoAS, and women had an even greater delay. Furthermore, delay in diagnosis is associated with worse functional outcomes in JoAS patients. The magnitude of the difference between the 2 groups in functional outcomes that we noted was small. To date there have been no studies performed to determine the functional significance of small differences in the BASFI scores. The BASFI total score is a mean of 10 subscales. To better understand the differences between groups in functional outcome, we compared the difference in the mean of each of these subscales between JoAS and AoAS patients. For each of these subscales, patients with JoAS scored higher than AoAS patients. The data presented in Table 2 indicates that those subscales that relate to lumbar spine and cervical spine movements had the largest differences between groups. Thus the clinical relevance of this may be that patients with JoAS have more severe axial symptoms than those with AoAS.
This observation is particularly important now, given that biologics are emerging as effective treatments for AS (13). Earlier diagnosis and treatment may improve long-term functional outcomes, but this awaits formal proof in prospective therapeutic trials with longer followup. There is a need for a higher index of suspicion among physicians so that patients with JoAS are diagnosed as early as possible. With the emerging role of magnetic resonance imaging as a diagnostic tool in AS, this may also facilitate a more prompt diagnosis.
There remain many unanswered questions that need to be addressed in future research efforts. It will be difficult to study the natural history of AS in the future as treatment with tumor necrosis factor blocking agents becomes more widespread. Therefore, identification of clinical prognostic markers will also be difficult. However, research efforts should focus on stratifying patients into prognostic categories so that therapy is initiated not only sooner, but also appropriately for each patient. Based on our results, it appears that JoAS is a progressive disease and is associated with worse functional outcome compared with AoAS. This would argue for a widespread campaign to educate physicians about the importance of early diagnosis and treatment of patients with JoAS. However, it remains unknown if treatment of patients early in the disease will prevent disease progression, and future studies should address this issue.