Inflammation at the insertion of ligaments, tendons, or joint capsules to bone, which is called enthesitis, is a distinctive feature of spondylarthropathy (SpA) (1, 2). It consists of focal, destructive microscopic inflammatory lesions which evolve toward fibrous scarring and new bone formation (2, 3). It may involve synovial and cartilaginous joints, syndesmoses, and extraarticular entheses (3, 4).
Peripheral enthesitis is observed in all SpA subtypes, including undifferentiated forms, and may sometimes present for a long period of time as an isolated clinical manifestation of an HLA–B27–associated disease (5). Several reports have pointed to enthesitis as a primary lesion in SpA, which may underlie all skeletal manifestations characteristic of these disorders, including synovitis (5–7). Besides SpA patients, enthesitis is also frequent among athletes as a consequence of traumatic injuries. However, in this case, it is not associated with intraarticular inflammation (i.e., synovitis). Peripheral enthesitis is usually revealed by clinical findings which lack specificity, such as localized pain, tenderness, and swelling, and there are no definite clinical criteria for the diagnosis of this manifestation. It may also be asymptomatic and detected only by imaging, such as conventional radiography, bone scintigraphy, magnetic resonance imaging (MRI), or ultrasonography (US) (4, 6–8).
In recent years, US has proved to be a highly sensitive and noninvasive tool, especially in the assessment of tendon and joint involvement (9–12). Several studies have described the use of B-mode US to identify the features of lower limb enthesitis in SpA (7, 13–15), revealing a high frequency of abnormal findings in asymptomatic entheses. More recently, power Doppler technology has allowed the visualization of abnormal vascularization and hyperemia of soft tissues in inflammatory articular diseases (16). Considering that enthesitis of SpA is underestimated and is often mistaken for sport and/or overuse pathology before the correct diagnosis is established, the aim of the present study was to use US in B mode associated with power Doppler to assess the prevalence and severity of peripheral enthesitis, including vascular changes, among the different subtypes of SpA. In addition, the prevalence of enthesitis was compared between SpA patients and control patients with mechanical low back pain (MBP) or rheumatoid arthritis (RA) to evaluate the specificity of entheseal involvement.
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- PATIENTS AND METHODS
Recently, the importance of peripheral enthesis involvement among the manifestations of SpA has been emphasized by several groups of investigators (2, 14, 28, 29) and is best reflected by its inclusion as a classification criterion for the diagnosis of SpA (18). However, peripheral enthesitis is commonly mistaken for other pathology and is most certainly underdiagnosed during the course of SpA.
To our knowledge, this is the first report of a systematic analysis of peripheral entheses by US examination in B mode combined with power Doppler in a large group of patients with the different SpA subtypes. There were several important findings in this study. First, the frequency of abnormal peripheral entheses was very high among SpA patients compared with controls. Second, abnormal entheses were uniformly found among SpA patients, irrespective of the disease subtype. Third, abnormal vascularization of affected entheses was detected exclusively in SpA patients. Finally, there was a trend toward a more severe pattern of US involvement in the peripheral forms of SpA.
In this study, the high prevalence of peripheral entheseal abnormalities detected by gray-scale combined with power Doppler US in SpA patients further outlines the primary significance of this finding among SpA manifestations. The greater sensitivity of US compared with clinical examination for the detection of SpA enthesitis was previously reported (13, 30) and was largely confirmed in the present study. In addition, we have shown that US assessment of inflammation at entheseal insertions could be dramatically improved by combining power Doppler with B mode, resulting in the visualization of a pattern highly specific for SpA. Thus, 98% of the SpA patients had at least one vascularized enthesitic site, compared with none of the controls.
So far, MRI has remained the imaging technique most widely applied in the assessment of musculoskeletal inflammatory processes. The MRI pattern of SpA enthesitis has been described as a diffuse bone edema adjacent to entheses, associated with surrounding soft tissue edema (31). However, this technique lacks sensitivity and specificity (8). This is because changes in the fibrous part of the enthesis, where fibroblasts are tightly cross-linked with little capacity for the accumulation of water, cannot easily be detected with MRI (8, 32). Since MRI is not appropriate and histologic assessment of enthesitis is not practical because of limited access, there is no “gold standard” for validating the US features of enthesitis.
In recent years, the capacity of power Doppler techniques to detect inflammation of musculoskeletal tissues, such as the synovial membrane, was reported (16). The performance of power Doppler in detecting low-velocity blood flow at the microvascular level in several tissues has been demonstrated (33, 34). In this study, the use of power Doppler US allowed us to detect abnormal vascularization of entheses in almost all SpA patients. Such abnormalities were primarily detected at the insertion of entheses to cortical bone and less frequently in bursae. We have previously reported such vascularization of enthesis insertion in 2 patients with SpA, with disappearance of this abnormality following efficacious therapy with anti–tumor necrosis factor α (anti-TNFα) (35). Abnormal vascularization was also previously described in the calcaneal bursa of 1 PsA patient (36). Nevertheless, this latter localization is not specific for SpA, since it can also be present in patients with mechanical enthesitis (37) or other inflammatory arthritides, such as RA. In contrast, vascularization of the body of the tendon and/or the junction between the tendon and the enthesis, which reflects tendinitis, was not detected in SpA patients in the present study (38).
The higher prevalence of enthesitis in the lower limbs, which was seen both in SpA and control patients in this study, has repeatedly been reported (13, 14, 39). This result is unlikely to reflect an overestimation of pathologic findings of US. Thus, normal US features and dimensions of entheses have been properly described by others, and we have used reported criteria for identification of abnormal features on US in B mode (15, 22, 23, 25, 26). It was suggested that the length, anatomy, and physiology of entheses may each contribute to such preferential distribution (13, 40). Thus, enthesitis, which could partly result from biomechanical stress forces, may happen where such forces predominate (i.e., at the distal entheseal sites of the lower limbs), both in inflammatory and mechanical diseases. Furthermore, such events might be amplified in the context of SpA (8). However, even in SpA, the US features of enthesitis were quite variable, suggesting that the importance of enthesitis could be graded according to the results of this imaging technique.
We adopted a 5-stage classification system that reflected our observations. Stage 1 presumably represented isolated vascular changes occurring during the initial phase of enthesitis. Stages 2a and 3a probably reflected increased vascular alterations associated with graded signs of morphologic alterations. Stages 2b and 3b, which were devoid of vascularization, were suggestive of inactive lesions. The relevance of this interpretation is supported by the monitoring of enthesitis showing 1) progression from stages 2a or 3a to stages 2b and 3b, respectively, during efficacious treatment of SpA with anti-TNFα, and 2) sequential progression from normal to stage 1, then to stage 2a, and finally to stage 3a during relapse after discontinuation of treatment (ref. 35 and D'Agostino M-A, Said-Nahal R, Dougados M, Breban M: unpublished observations).
We detected no major differences in the frequency or categorized localization of peripheral enthesitis by US between the different SpA subtypes, even when according to the clinical distribution of skeletal symptoms (i.e., axial, peripheral, or mixed). In contrast, a higher severity of US-identified enthesitis seemed to be associated with a predominantly peripheral clinical presentation. Taken together, these observations are consistent with the concept that different subtypes of SpA represent phenotypic variations of a unique disease (41, 42). Furthermore, the poor reliability of clinical findings in detecting enthesitis could explain some degree of the inadequacy inherent in SpA classification based only on clinical presentation.
We have reported here the results of a cross-sectional study performed on patients with established diagnoses. Since the recruitment was hospital based, the patients included here may have had more severe disease than that observed in the general SpA population. This could have contributed to the high prevalence of inflammatory enthesitis detected with US. To evaluate the diagnostic value of gray-scale combined with power Doppler US techniques, it will be necessary to conduct a longitudinal study including patients with early disease and still-uncertain diagnoses. It is also well established that the performance of power Doppler US can be influenced by the examiner, the machine, and the acoustical conditions involved in image processing. In the present study, all parameter settings were kept stable to optimize the intraobserver reliability of the technique. Indeed, intra- and interobserver reliability assessed on saved images was satisfactory. However, to validate this technique as a potentially useful tool for both the diagnosis and followup of SpA, it will also be necessary to assess the interobserver reliability of examination.