Background
Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease affecting up to a third of psoriasis patients [
1,
2]. PsA can affect different locations including the synovial joint, bone, fat pad, bursa, adjacent tendons, and entheses [
3]. Enthesitis is a unique feature of the spondyloarthritis (SpA) disease group in general, and of PsA in particular [
4,
5]. Clinical enthesitis is a common finding occurring in a third of PsA patients [
6,
7].
There are a few imaging modalities that can assist in enthesitis assessment apart from physical examination. Conventional radiography, which usually shows erosions at the enthesis and enthesophytes [
8], is limited by its ability to detect mainly chronic irreversible bone damage rather than active inflammation. Another modality is magnetic resonance imaging (MRI) that can demonstrate both active lesions, as entheseal thickness, soft tissue edema, and adjacent bone marrow edema, as well as chronic lesions including erosions and enthesophytes [
9]. However, in a recent study that evaluated whole-body MRI, enthesitis was found in only 18% of the patients with PsA and the ability to read images from some locations was technically limited [
10]. Musculoskeletal ultrasound (US) assessment is inexpensive, readily available, relatively easy to perform and can evaluate a number of entheseal locations in a short period of time [
11]. Several studies found higher sensitivity and specificity of US assessment of the entheses compared with clinical examination [
12‐
15]. Therefore, US has emerged as the preferred modality to assess enthesitis.
The primacy of enthesitis in the pathogenesis of SpA and PsA is a matter of debate. According to the synovio-entheseal model, suggested by McGonagle et al. enthesitis is the initial site of musculoskeletal inflammation in SpA [
16]. A few animal model studies support this hypothesis by reporting a link between mechanical stress, enthesitis, and the development of arthritis that is similar to PsA [
17‐
19]. In addition, in a small study that followed 30 psoriasis patients for 3.5 years, the presence of sonographic features of thickness of the quadriceps tendon predicted the development of PsA [
20]. However, overall there is limited information about the association between enthesitis and disease outcomes in patients with PsA. We hypothesized that since enthesitis play a role in the pathogenesis of PsA it may serve as a marker of more severe disease outcomes in PsA, alternatively, enthesitis may play a direct role in the development of joint damage in PsA.
Hence, the main objective of the present study was to examine the association between sonographic enthesitis and the severity of radiographic features of damage in the peripheral and axial joints in patients with PsA.
Discussion
It was Ball in 1971 who primarily set the foundations for the significance of enthesitis in SpA, by suggesting that the enthesis is centrally affected in ankylosing spondylitis (AS) patients, while the synovial joint is the main target of the inflammatory involvement in rheumatoid arthritis (RA) patients [
29]. A few decades later, McGonagle and colleagues contributed significantly to the understanding of enthesitis as a key feature in SpA [
16,
30]. Over the years, this idea was recognized by different organizations as the Assessment of Spondyloarthritis International Group (ASAS) that included it in their classification criteria for both axial and peripheral SpA and by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) who included it in the stem requirements of the CASPAR criteria [
21,
31,
32].
The current study provides novel data regarding the association between enthesitis and features of severity in patients with PsA. The study found that a higher MASEI score, which reflects more severe enthesitis, is associated with severity of peripheral radiographic joint damage as measured by mSS. Furthermore, the severity of enthesitis was associated with proliferative and erosive features of joint damage including joint ankylosis, arthritis mutilans and periostitis. Additionally, a higher enthesitis score was associated with features of axial radiographic damage, including syndesmophytes and sacroiliitis.
According to the synovio-entheseal complex model, enthesitis is the primary lesion that triggers the related inflammation in the adjacent synovial joint [
16]. This hypothesis is supported by a study that compared early SpA to early RA patients and demonstrated that knee synovitis was associated with entheseal abnormalities only in the SpA group [
33]. Additional studies from the same group found associations between enthesitis and various features of SpA as dactylitis, tenosynovitis, arthritis mutilans, distal interphalangeal joint involvement, and psoriatic nail disease [
34]. Supporting the importance of enthesitis in peripheral musculoskeletal inflammation in PsA, other studies that compared PsA and RA patients found that sonographic entheseal abnormalities in the fingers were identified only in the PsA group [
4,
5]. Finally, a recent study in transgenic TNFα mice demonstrated that the initial signs of inflammation were found at the entheses and subsequently new bone formation appeared at entheseal sites and correlated with the degree of inflammation [
19]. In accordance with these findings, our study found an association between the extent of enthesitis and peripheral joint damage.
However, there are studies that could not confirm the specific link between enthesitis and SpA [
35,
36]. Paramarta et al. found the same prevalence of entheseal involvement in SpA and RA patients [
35]. Ibrahim et al. found similar sonographic entheseal scores in patients with PsA and RA [
36]. However, the significantly older age of the RA group in their study may have accounted for the higher entheseal score in this group leading to the similarity in scores. Overall, the discrepancies between the different studies can be attributed to the lack of standardization manifesting with diversity in several aspects including the type of the patients, the sample size, disease manifestations, enthesitis sites scanned, sonographic indices, and imaging equipment.
Unfortunately, there are only a few longitudinal studies that may address the controversy regarding the primacy of enthesitis in the pathogenesis of SpA [
20,
37]. Tinazzi et al. found that thickness of the quadriceps tendon predicated the development of clinical PsA in a small cohort of psoriasis patients [
20]. El-Miedany et al. evaluated 126 psoriasis patients by clinical, radiological and sonographic measures over a period of 1 year [
37]. However, this study did not differentiate between the two pathologies as it found that both sonographic enthesitis and synovitis at baseline were predictors of joint damage in new-onset PsA patients. Finally, a recent study in 41 psoriasis patients found that arthralgia and baseline MRI synovitis in the hand joints predicted the development of clinical PsA after 1 year of follow-up [
38]. The detection of periarticular inflammation in only 4% of the patients raises a question regarding the reliability of this tool for enthesitis evaluation.
Enthesitis is a widespread condition that can involve the peripheral as well as the axial skeleton. The location of inflammation in spondylitis is at the entheses, where the ligaments attach to the vertebrae [
39]. Several studies showed an association between clinical enthesitis [measured by the Maastricht Ankylosing Spondylitis Enthesis Score (MASES)] and both higher disease activity [measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] and worse functional status [
40,
41]. In addition, Muche et al. reported that enthesitis in the sacroiliac region, as detected by MRI, was more common in advanced sacroiliitis [
42]. Our study found an association between sonographic enthesitis and axial damage, including both spondylitis and sacroiliitis. In contrast to our study, Alcalde et al. did not find a correlation between sonographic enthesitis and radiographic sacroiliitis [
43]. However, their study is not entirely comparable to ours for several reasons: first, the study population included AS and not PsA patients, second, the sample size was much smaller including only 44 patients and lastly, the sonographic enthesitis index included less entheseal sites and did not include Power Doppler vascularization assessment.
The agreement between sonographic and clinical assessment of enthesitis is an area of interest in rheumatology due to the limited specificity and sensitivity of the latter method [
15]. A few studies that compared these two modalities found low to moderate agreement [
43,
44]. Recently, van der Ven et al. reported that adding US evaluation in psoriasis patients who had entheseal tenderness on clinical examination reduced the rate of enthesitis by 64% [
45]. In this regard, it should be mentioned that the MASEI score includes entheseal lesions that represent irreversible damage from prior active enthesitis, such as enthesophytes and erosions, in addition to active lesions such as vascularization. Thus, the sonographic score may be high in patients who sustained entheseal damage from prior enthesitis who may be in remission at the time of assessment.
This study has several limitations. First, the association between sonographic enthesitis in sites located adjacent to large joints and radiographic damage of small joints in the hands and feet is indirect and may not suggest a causal link. Identifying enthesitis in the small joints is a difficult task, which may explain why there is no such enthesitis index. In addition, radiographic damage in large joints is less common and hence there is no standardized damage index for these sites. Thus, although the study cannot support a direct causal link between enthesitis and the development of peripheral or axial joint damage, the strong association observed between the extent of enthesitis and a number of features of joint damage in the peripheral and axial joints suggest that enthesitis may be a marker of more severe PsA phenotypes. An additional limitation of the study includes its cross-sectional nature that does not allow making causal inferences. Furthermore, we assessed the associations between enthesitis at a single time point and radiographic damage that has accumulated over time. However, MASEI score includes a bone damage subcategory which reflects irreversible entheseal bone damage (e.g., enthesophytes and erosions) that has accumulated over time. Furthermore, all regression analyses showed that these chronic bone lesions were more strongly associated with radiographic joint damage than the soft tissue lesions. Lastly, treatments may have modified the relationship as we controlled for treatment only at the time of assessment, although it is expected that effective treatment for enthesitis, such as biologics, would have weakened the association. However, our sensitivity analyses that included the use of biologics and DMARDs at any point during the disease did not significantly modify the results.
This study has several strengths. To our knowledge, this is the largest study thus far that explored the association between sonographic enthesitis and radiographic joint damage in PsA. The use of sonographic enthesitis as a primary predictor improved the accuracy of assessing this important feature over physical examination [
15]. In addition, the PsA cohort in this study is well phenotyped, which enables to control for multiple confounders.