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- PATIENTS AND METHODS
The term spondylarthropathy (SpA) refers to a group of inflammatory rheumatic disorders that currently is di- vided into distinct diagnostic entities: ankylosing spondylitis (AS), which is characterized by predominant axial skeletal involvement and advanced radiographic sacroiliitis; a subset of psoriatic arthritis; arthritis associated with idiopathic inflammatory bowel diseases; reactive arthritis (ReA), which is characterized by an antecedent triggering infection; and undifferentiated SpA, which is defined by the lack of any of the former distinguishing features. A close relationship between the different SpA subtypes is supported by several observations, including anatomic studies of the skeletal lesions that have isolated enthesitis as a characteristic feature of SpA (1–3) and the role of HLA–B27, a genetic predisposing factor shared by the different varieties of SpA (4). There is, however, some difficulty in establishing a formal distinction between subtypes as defined above because of frequent overlapping presentations in individual patients. Hence, the SpA spectrum refers to the variety of skeletal and extraarticular inflammatory manifestations that may combine differently among patients (5, 6). This set includes axial manifestations (spinal and buttock pain or stiffness, radiographic sacroiliitis), peripheral arthritis, dactylitis, peripheral enthesitis (such as subtalar pain), acute anterior uveitis, psoriatic lesions, and inflammatory bowel disease (IBD; i.e., Crohn's disease, or ulcerative colitis).
A classic interpretation of the interrelationship between SpA phenotypes is that they result from different combinations of factors that contribute independent of each other to produce overlapping diseases (7). Such interpretation was supported by studies reporting that conditions such as AS and ReA breed true within families (8, 9), but not by our recent analysis of a large collection of French SpA multiplex families (10, 11). In the latter study, all possible SpA subtypes were represented among the patients. Nevertheless, axial skeletal involvement appeared almost constant. Furthermore, all the manifestations belonging to the spectrum of SpA appeared linked together and to HLA–B27 within families (11). Hence, neither articular or extraarticular SpA features segregated independent of each other, as predicted if independent factors were determining those manifestations. Our results supported a novel model in which a critical core of predisposing factors, including HLA–B27, were shared by different forms of SpA, whereas secondary factors determined phenotypic variations. Thus, SpA appeared more homogenous than previously thought, and we concluded that SpA subtypes should be considered as phenotypic variations of a unique disease rather than truly different conditions (11). One major consequence of this conclusion is that SpA should be studied as a whole for the purpose of genetic studies. This prediction allowed us to successfully map a non-major histocompatibility complex locus linked to SpA predisposition in multiplex families (12).
In our study, the significance of diversity among familial SpA was previously addressed by examining the clustering of SpA manifestations among families, and we found that extraarticular manifestations, such as psoriasis, appeared evenly distributed, which in turn suggested that factors influencing the occurrence of this manifestation were ubiquitous. In contrast, we found some degree of familial clustering both for peripheral arthritis (10) and for arthritis associated with IBD (4), as if specific predisposing factors were influencing those manifestations. Finally, uveitis could not be analyzed with confidence because of its dependence on disease duration. Nevertheless, it was clear that SpA tended not to aggregate among families as distinct entities. Hence, the classic subtypes that have been defined until now may not represent adequate subdivision. This assumption is more likely to be true that radiographic sacroiliitis, which has been taken as an essential distinction criteria, is highly dependent on disease duration.
The aim of the present study was to determine if any of the elementary manifestations that are part of the SpA spectrum combine in an orderly fashion, and whether this would lead us to propose a model of discrimination between SpA phenotypes different from the classic one. To achieve this goal, the phenotypic presentation of the disease in the context of familial SpA was thoroughly analyzed by means of clustering methods.
- Top of page
- PATIENTS AND METHODS
The early description of entities such as AS, psoriatic arthritis, and ReA reflected the most striking presenting symptoms of patients. However, these categories were not expected to necessarily best reflect the underlying pathogenesis. Most intriguing was the early recognition of frequent clinical overlap between subsets, which eventually led to develop the SpA classification criteria (5, 6).
By studying familial SpA, we observed the relative inadequacy of the current subclassification to describe meaningful differences between patients (4). Here, we tried to generate a more appropriate description of phenotypes by performing pattern analysis. The principle of this study was to examine the combination of elementary manifestations that are recognized as part of the SpA spectrum, rather than the classic subtypes. From multiple correspondence analysis, we inferred that the few B27-negative individuals (about 3% of the whole set) were quite different from the rest of the population, and we decided to exclude them from further analysis to improve internal consistency. We could also observe some trends toward grouping of axial manifestations on one side and of peripheral skeletal manifestations and psoriasis on the other, whereas IBD separated from the rest of manifestations.
As a limitation, this first method could not take in account continuous variables, such as age at onset or disease duration. However, age at onset could influence disease presentation (23). Therefore, it was included among variables studied in the cluster analysis. Such variables as radiographic sacroiliitis, uveitis, and IBD appeared to increase in parallel with disease duration and were then excluded from the algorithm used to elaborate clusters. Moreover, in this type of cross-sectional retrospective study, disease duration is linked to some bias: 1) long disease duration correlates with young age at onset, as a consequence of left censoring; 2) long disease duration associates with increase in the risk of missing remitting manifestations, such as peripheral arthritis, peripheral enthesitis, dactylitis, and uveitis, which were routinely retrieved from medical history; and 3) disease duration would seem to affect presentation of the disease if the natural history of disease was changing over time. Therefore cluster analysis was limited to the 504 HLA–B27 patients with known disease duration, which were split into 3 groups of 150–200 patients each, spanning distinct disease duration intervals. Advantages in performing separate analyses in these subgroups were that analysis performed in the groups with the shortest disease duration were less sensitive to left sensoring effect and that consistency of the classification could be tested by comparing results obtained in several samples from the same original population.
In both groups with the shortest disease duration (1 and 2), the nonhierarchical cluster method classified patients into 2 major clusters (A and B), with quite similar characteristics. A majority of the women fell into the A clusters (65% altogether), whereas a majority of the men were in the B clusters (65%). Clusters A and B were very similar regarding axial symptoms, radiographic sacroiliitis, uveitis, and IBD. However, both B clusters were characterized by a younger age at onset and a higher frequency of peripheral arthritis, dactylitis, and psoriasis than the A clusters. The high similarity of results obtained in 2 independent sets of patients, with distinct diseases durations, was quite remarkable and unexpected to happen by chance. Reproducibility of the classification was also assessed by bootstrap resampling of the nonhierarchical method and by applying a hierarchical cluster Ward's method, both of which showed a good reproducibility of the clusters selected in groups 1 and 2. Interestingly, the best reproducibility was achieved in group 1, which was the least sensitive to the bias inherent to long disease duration.
Few variables segregated differently between clusters in group 2, as compared with group 1. The proportion of men and women in each cluster was more balanced in group 1 than in group 2, in which a large majority of men fell into cluster B and a majority of women into cluster A. This should be interpreted along with the increased proportion (+25%) of men in group 2 as compared with group 1. This observation could possibly be explained by a left censoring effect, according to which group 2 was enriched in patients with early onset (as shown by a younger average age at onset in this group compared with group 1), and thereby in men from cluster B. Peripheral enthesitis differed strikingly between clusters A and B in group 1 but not in group 2. However, this manifestation was also one of the most difficult to assess with confidence, especially in the group with the longest disease duration.
Clusters generated in group 3 were more difficult to interpret, and correspondence with those generated in both former groups was not straightforward. Hence, 3 clusters were generated, both by nonhierarchical and by hierarchical methods. However, bootstrap resampling produced with equal frequencies 2 and 3 clusters. One major variance with groups 1 and 2 concerned the early age at onset in all 3 clusters, which was similar to clusters 1B and 2B. This was expected as a consequence of left censoring, but questions the true significance of clusters formed in group 3. Nevertheless, most variables opposed cluster A to clusters B and C, except for clinical axial manifestations and uveitis (which were similar between the 3 clusters) and psoriasis (which was the main distinguishing feature between clusters 3B and 3C).There were several arguments to indicate that clusters 3B and 3C indeed corresponded to clusters 1B and 2B. The misclassification rate was improved during bootstrap resampling by combining the 2 former clusters. Furthermore, discriminant analysis was used to derive a classification model based on the 2 groups of shorter disease duration. When this model was applied to the third group, a large majority of clusters 3B and 3C fell into new cluster B. In contrast, cluster 3A was almost equally divided between new clusters A and B (suggesting the possibility that left censoring might have affected the formation of cluster 3A).
From these analyses, it appears that 2 major clusters were consistently described. The first one would correspond to a rather pure axial disorder with a relatively late age at onset. The second would correspond to a more diffuse pattern of disease with a high proportion of peripheral enthesitis, arthritis, dactylitis, and psoriasis. Both clusters appeared rather similar with respect to the prevalence of uveitis and radiographic sacroiliitis. There remains some uncertainty about sex distribution between clusters because women were more prevalent in the A clusters, in group 1, and above all in group 2, but not in group 3. However, due to the left censoring, it is possible that data in group 3 were less interpretable than in both former groups. The place of IBD also remains unclear because this manifestation was selective for cluster B according to data from group 3 but not from group 2. Only a prospective study could reliably help clarify these points. Interestingly, patients in cluster B might have been classified as having ReA if low stringency criteria were used (i.e., not requiring a recent proven triggering infection) (24). Interestingly also, characteristic features of cluster B, i.e., a young age at onset, peripheral arthritis, dactylitis, and psoriasis, have been identified as severity markers of SpA (23, 25). Then, the 2 clusters of SpA that were described in the present study could correspond to severity subsets. Their mild degree of familial aggregation, which was statistically significant, strongly suggests that these phenotypes are likely determined by widespread genetic factors. Consistently, heritability of age of onset and severity have previously been demonstrated in AS (26, 27). If this hypothesis is correct, it could also explain the previously reported true breeding of AS and ReA within families (8, 9). Furthermore, cluster assignment could be useful in genomescan analysis to map genes responsible for the diversity of SpA expression, and also for its severity.
Possible limitation of this study relates to the familial form of the disease, which may not adequately represent the general SpA population. Nevertheless, it should be mentioned that a recent survey found the familial form may account for as many as 50% of all SpA patients (E. Dernis-Labous et al, personal communication), and that no major phenotypic difference was identified between familial and sporadic cases in previous studies (4). Also noteworthy, the present study focused on the HLA–B27-positive patients because too few HLA–B27-negative patients were available. Then, additional studies will be necessary to determine if the model of classification proposed herein applies to other populations of SpA, including sporadic and HLA–B27-negative cases.