Abstract
Psoriatic arthritis (PsA) affects up to 30% of patients with psoriasis and may include musculoskeletal manifestations such as enthesitis. Enthesitis is associated with joint damage, and early detection and treatment are essential to management of the disease. Traditionally assessed by clinical examination and conventional radiography, entheseal inflammation can now be more accurately assessed earlier in the disease using techniques such as ultrasound, magnetic resonance imaging, computed tomography, and molecular imaging. However, there is little consensus on the optimum definition for diagnosing enthesitis in PsA or on the ideal scoring system for measuring response to treatment. This review aims to summarize the benefits and limitations of different imaging modalities in the assessment of enthesitis. It also proposes that adoption of standardized definitions and validation of scoring systems and imaging techniques in clinical trials will allow the efficacy of new treatment options to be assessed more accurately.
Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects up to 30% of patients with psoriasis1,2. Musculoskeletal manifestations of PsA may include peripheral arthritis, spondylitis in the spine, and enthesitis and/or dactylitis. PsA can affect multiple types of soft tissue and has a variable presentation of synovitis, which is commonly asymmetrical3.
About 60–80% of patients with PsA will develop enthesitis1, defined as inflammation of the entheses, the areas where tendons, ligaments, or joint capsules insert into the bone2. Enthesitis is one of the first signs of disease and has been proposed to be the primary lesion in PsA4, a finding that has led to its inclusion in the Classification Criteria for Psoriatic Arthritis (CASPAR)5 and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) core disease domains for PsA6. Enthesitis is also associated with joint damage and is an indicator of disease severity1. The importance of enthesitis is further highlighted by its inclusion in the Outcome Measures in Rheumatology (OMERACT) PsA core domain set, warranting evaluation in clinical trials and observational studies of PsA7.
Early diagnosis and treatment of PsA are critical given that delays in rheumatologic assessment by ≥ 6 months are associated with longterm radiographic progression and detrimental functional outcomes8. Therefore, identifying enthesitis, a marker of early disease, can lead to early treatment initiation before irreversible structural damage occurs2. However, identifying enthesitis in the clinic can be challenging, and incorporating imaging modalities in the assessment of enthesitis may be useful.
This narrative review describes imaging modalities used to detect enthesitis and discusses ways in which standardized definitions and validated scoring systems and imaging techniques will allow a more accurate assessment of treatment options. We include relevant information identified from a targeted literature search (Supplementary Data 1, available with the online version of this article) focused on PsA, enthesitis, and the imaging techniques used in the assessment of enthesitis.
Clinical assessment and imaging techniques used to assess enthesitis
Clinical assessment
Palpation is used to detect the presence of local tenderness and soft tissue swelling in the clinical examination of enthesitis9 (Figure 1A). Physicians apply pressure to each site with the dominant thumb, until the nail bed blanches, asking patients to provide subjective reports of tenderness10. Several indices have been developed to help standardize the clinical diagnosis of enthesitis2,11,12 (Table 1A), although only the Leeds Enthesitis Index (LEI) has been specifically developed for PsA11.
A. Nail changes, dactylitis, and distal interphalangeal joint (DIP) subluxation, as seen during clinical examination. B. Conventional radiographs of the same patient, exhibiting “wispy periostitis,” and DIP subluxation (indicated by the arrow). C. Ultrasound providing a longitudinal view of the DIP extensor tendon (indicated by the triple asterisk), showing enthesitis in the hand (extensive cortical irregularity indicated by the downward arrow; DIP joint indicated by the upward arrow). Synovial effusion at the DIP joint can be seen (indicated by the double asterisk) as can synovial hypertrophy (single asterisk). D. Power Doppler ultrasound showing the same area of damage as panel C, with Doppler signal indicating active inflammation around the cortical irregularity.
Clinical indices used in the assessment of enthesitis.
Assessing enthesitis by clinical examination is noninvasive, inexpensive, and relatively fast, and can be conducted as needed without onward referral or access to specialized equipment or facilities. However, clinical identification of enthesitis can be challenging. Assessments are dependent on subjective reports by the patient and physician and do not provide complete information on the extent of entheseal involvement or the presence of subclinical enthesitis9.
Moreover, tenderness over an entheseal area can also be present in conditions that mimic enthesitis, such as tendinitis or mechanical injury, making a clinical diagnosis subject to false-positive results2.
Conventional radiography
Clinical examination can be combined with conventional radiography9. Typical radiographic features visible in entheses of patients with PsA include enthesophyte formation, new bone formation, and bony irregularities13 (Figure 1B). Radiography is also particularly useful for monitoring syndesmophytes in spinal entheses14.
The cost of taking conventional radiographs is low, as is the need for specialized facilities. However, radiographs do not reveal inflammation in soft tissue structures; hence, only damage associated with chronic enthesitis, and not early disease, is visible2,13,15. Therefore, the usefulness of radiography for diagnosing enthesitis in early PsA is limited2,13,15. Similarly, the benefits of using radiography to monitor enthesitis in peripheral sites are limited. These limitations have highlighted the need for more sensitive imaging techniques in the assessment of enthesitis.
Ultrasound (US)
US is widely used because it is inexpensive and accessible, is nonionizing and noninvasive, and produces real-time images, allowing documentation of clinical information at the point of care with minimal risk of harm to the patient2,16. Most published US studies in PsA have focused on the entheses of the lower extremities; however, more recent scoring systems have incorporated upper-extremity entheses, recognizing the confounding factors of body weight and biomechanics on the lower-extremity entheses17. Greyscale US (Figures 1C, 1D, 2A, and 2B) can detect both acute (e.g., increasing thickness, hypoechogenicity) and chronic inflammation or changes (e.g., erosions, enthesophytes)18. These components, including chronic changes, have recently been reported to be part of the definition of enthesitis19,20 and may be important for differentiating patients with PsA from those without disease20. A sonographic Doppler signal (Figure 1D) can be used to detect active inflammation, evidenced by abnormal vascularization20 (Figure 2C and 2D). It has also proven useful in identifying subclinical involvement of entheses prior to development of symptoms20,21,22. A consensus definition of enthesitis by US assessment was recently proposed by the OMERACT US Working Group (UWG) and states that enthesitis is a hypoechoic and/or thickened insertion of the tendon within 2 mm of the bony cortex, which exhibits a Doppler signal if active, with possible erosions and enthesophytes/calcifications as signs of structural damage19,22. However, defining enthesitis as being within 2 mm of the bony cortex remains an area of active debate, with the GRAPPA UWG maintaining that the enthesis boundary could also extend beyond this cutoff or to within the adjacent bursa20. This is consistent with the concept of the “enthesis organ” or the “synovio-entheseal complex” that comprises more than the joint insertion site alone and includes the nearby synovium23; thus, the OMERACT UWG’s current definition may not fully identify all the inflammatory changes due to enthesitis.
A. A large enthesophyte (as indicated by the arrow) as well as significant retrocalcaneal bursitis and bursal synovitis (as indicated by the double asterisk). Retrocalcaneal bursal effusion can also be seen (as indicated by the single asterisk). B. Achilles enthesitis that includes large erosions (as indicated by the arrow) and cortical irregularities. C. Significant bone proliferation of the calcaneus (indicated by the arrows), as well as tendon hypoechogenicity, thickening, and loss of fibrillar echotexture. D. Active inflammation as indicated by Doppler signal, located at the distal portion of the Achilles tendon.
Several scoring systems have been devised for enthesitis assessment by US2,19,20,21,24,25,26,27,28 (Table 1B). The OMERACT UWG Enthesitis Score was developed in conjunction with the consensus definition of enthesitis. This scoring system emphasizes defining lesions at the enthesis as being within 2 mm of the cortical bone and those outside the enthesis as being in the tendon or bursa, as well as the benefit of scoring each component as present or absent19 (Table 1B). The GRAPPA UWG is also working on a scoring system designed specifically to assess enthesitis in PsA for diagnostic purposes20. The GRAPPA UWG identified 5 lesions and 6 entheseal sites (Table 1B) as being critical for identifying patients with PsA and is currently working on validating and finalizing the scoring method20.
Ultrasound scoring scales used in the assessment of enthesitis.
Other US scoring methods have been used to assess enthesitis for diagnosis and entheseal response to treatment (Table 1B). Although most scoring systems have a reasonable level of reliability and sensitivity, they were developed and evaluated in spondyloarthritis (SpA) rather than PsA specifically7. Additionally, most of these approaches also have a strong focus on entheses in the lower extremities of the body, which may be confounded by mechanical changes caused by aging, physical activity, and obesity7,29.
Some limitations associated with US in the assessment of enthesitis include its inability to identify any intraosseous abnormalities associated with active enthesitis30 and the lack of guidelines regarding Doppler settings for enthesitis imaging. Further difficulties involve standardization of settings on different machines9 and weak signals and artifacts due to the small number of blood vessels in entheses and proximity to bone21; however, visualizing avascular fibrocartilage at entheseal sites with US is possible31.
Magnetic resonance imaging (MRI)
MRI is a powerful nonionizing imaging technique that can be used to evaluate axial or peripheral entheses2,15. MRI sequences for enthesitis evaluation typically are T1 weighted, T2 weighted with fat suppression or short-tau inversion recovery, or T1 weighted with fat suppression after contrast administration30. Because of its ability to detect small differences in water content between adjacent tissue types, MRI can detect early signs of enthesitis that are not visible using radiography15. It can provide high-resolution evidence of soft tissue abnormalities such as thickening of tendons and ligaments, joint effusions and inflammation, bone erosions, enthesophytes, and intraosseous bone marrow edema30 (Figure 3A–3C).
A. Short T1 inversion recovery magnetic resonance imaging (MRI) showing high signal intensity at the Achilles tendon insertion (enthesitis, indicated by the yellow arrow) and bone marrow edema (short thin arrow). Long thin arrow shows high signal intensity in the synovium of the ankle joint (synovitis). Image reproduced with permission from McQueen F, et al. Arthritis Res Ther 2006;8:207. © BioMed Central Ltd 2006. B. T1-weighted, contrast-enhanced MRI showing inflammation at enthesis (indicated by the yellow arrow) and bone erosion at the tendon insertion (short thin arrows). Image reproduced with permission from McQueen F, et al. Arthritis Res Ther. 2006;8:207. © BioMed Central Ltd 2006. C. Dynamic contrast-enhanced MRI technology superimposed on an axial T1-weighted dynamic MRI of the wrist showing tenosynovitis. The wrist synovial membrane is outlined in blue (joint synovial membrane compartment indicated by SYN) and regions around the tendon sheaths are yellow (first to third extensor compartment indicated by EI-III, first and second flexor compartment indicated by FI-II). Reprinted with permission from The Journal of Rheumatology, Cimmino MA, et al. J Rheumatol Suppl. 2012 Jul;89:44–8. All rights reserved. D. Whole-body MRI enables visualization of multiple potential sites of enthesitis in 1 scan but at a lower resolution than conventional MRI. Østergaard M, et al. Best Pract Res Clin Rheumatol 2016;30:624–37. Copyright 2008, reprinted with permission from Elsevier.
The PsA MRI Score (PsAMRIS) is the most studied scoring system for measuring destructive and inflammatory changes in the hands and feet in PsA; however, it is not specific for assessing enthesitis32,33. PsAMRIS was devised by the OMERACT MRI Working Group and has been shown to have good intrareader and interreader reliability29,33. PsAMRIS includes measures of synovitis, tenosynovitis, periarticular inflammation, bone marrow edema, bone erosion, and bone proliferation32. Further application of PsAMRIS in randomized controlled trials of PsA is warranted29.
Given the lack of MRI scoring systems for evaluating enthesitis, the OMERACT MRI in Arthritis Working Group recently developed the Heel Enthesitis Scoring System (HEMRIS) for use in patients with SpA or PsA34. Both inflammatory and structural MRI findings were included, with HEMRIS showing good interreader agreement for status scores and for changes in inflammatory variables over time. Notably, the heel enthesitis score was especially reliable when the mean score of 2 readers was used, an approach that is typically used in clinical trials. Overall, HEMRIS is a promising tool, and validation in clinical trials will be important.
Whole-body (WB) MRI is a novel approach that allows visualization of the entire body in 1 examination but has lower image resolution than conventional MRI33 (Figure 3D). A proof-of-concept study showed that enthesitis was the most common pathology detected by WB-MRI and that significantly more locations of enthesitis were identified with WB-MRI than with clinical examination35. GOLMePsA, an ongoing trial of golimumab and methotrexate in early PsA, is expected to provide data on the role of WB-MRI as an outcome measure by assessing the effect of treatment on inflammation as visualized using WB-MRI and US36. However, WB-MRI carries some limitations. For instance, subtle enthesitis can sometimes only be visualized following administration of contrast media35. Additionally, agreement between WB-MRI and clinical examination is often < 50%, and readability and reproducibility of WB-MRI for distal peripheral joints are low because of poor resolution. Thus, further clarity surrounding the generalizability of this technique for detecting enthesitis is required37,38.
The OMERACT MRI Working Group has taken the first steps toward standardizing the process of WB-MRI, including image acquisition and definitions of key pathologies and has developed a preliminary OMERACT scoring system for the assessment of inflammatory arthritis using WB-MRI39. The GRAPPA MRI Working Group has also been investigating outcome measures for trials in PsA and is proposing to conduct a longitudinal, multicenter, and preferably randomized treatment study in patients with active PsA that will assess WB-MRI of peripheral and axial joints and entheses according to the OMERACT recommendations24. The study will also incorporate assessment of feet and hands using PsAMRIS, as well as knees and hips using Knee and Hip Inflammation MRI Scoring Systems24.
Newer MRI techniques have also been developed. Diffusion-weighted imaging MRI is a technique based on the Brownian motion of water, which is reduced in inflammation15. Diffusion-weighted imaging MRI provided good differentiation between active and inactive ankylosing spondylitis; however, enthesitis and synovitis were not evaluated, and further studies are needed to assess the usefulness of this technique40. Ultrashort echo time MRI (UTE MRI) has also been investigated because it allows changes at the entheses to be viewed at higher resolution and earlier than conventional MRI41. One study has shown that UTE MRI can be used for morphological and quantitative evaluation of entheses in patients with PsA41.
Despite the benefits described above, MRI has many limitations. It is expensive and time consuming and often requires referral to specialist facilities. MRI examinations are not suitable for patients with claustrophobia, pacemakers, or metal implants15. Further, MRI may result in adverse effects from the administration of contrast media (e.g., nephrogenic systemic fibrosis in patients with renal insufficiency, allergic reaction). MRI cannot always exclude enthesitis; owing to limited water accumulation, MRI signals are often low in structures that make up the entheses42. Therefore, MRI alone may not be sufficient to consistently detect clinically meaningful changes in enthesitis43. For instance, in the HEEL study of etanercept versus placebo in patients with SpA and heel enthesitis, significant improvement was observed with etanercept by clinical assessment using patient’s global assessment but not by MRI43. However, the trial size was small and only calcaneal bone marrow edema was considered43. The development and use of composite scoring systems such as HEMRIS may improve the utility of MRI in PsA.
Computed tomography (CT) and scintigraphy
CT has high spatial resolution and can detect structural changes, such as erosions. However, standard-resolution CT imaging is limited in its ability to detect synovial inflammation owing to poor iodine contrast resolution, and longitudinal data regarding its usefulness in diagnosing and monitoring enthesitis are lacking44. Dual-energy CT iodine mapping, which improves iodine contrast resolution, has a higher spatial resolution than MRI and has shown promise in detecting inflammatory lesions, especially lesions in small joints (e.g., distal interphalangeal joints)45,46. Additional studies are needed to determine the role of this technique in the diagnosis of early-stage PsA and assessment of therapeutic effects. Positron emission tomography (PET)/CT using 18F-fluorodeoxyglucose (FDG) may also be of value given that a retrospective study found high accumulation of FDG in the entheses of patients with SpA47. In that study, PET/CT-FDG had a higher sensitivity for evaluating enthesitis than MRI; however, this was a small-scale, retrospective study, and further studies are needed.
Scintigraphy can also be used in PsA; radioisotopes that selectively bind to specific tissue types are taken internally, and the radiation they emit is recorded by external detectors. However, because of a lack of specificity, scintigraphy has been largely replaced by US and MRI35,44. Immunoscintigraphy aims to improve on the current technique by using a radiolabeled tumor necrosis factor (TNF) inhibitor [certolizumab pegol (CZP)] to detect TNF-α–driven inflammation in vivo48. A recent study found that peripheral and axial inflammation could be detected in patients who received intravenous injections of radiolabeled CZP, with a strong correlation with therapy response: joints with no uptake of the tracer were more likely to remain tender despite treatment with CZP48. These newer imaging modalities are promising but carry the limitation of exposing patients to radiation. Further evaluation of these modalities is necessary.
Using imaging to monitor treatment response in clinical trials
Multiple clinical trials have assessed the efficacy of biologic and small-molecule drugs in the treatment of enthesitis in PsA2. However, the number of patients within these trials who have enthesitis at baseline varies widely (24–83%)2. That is because patients with PsA are generally enrolled into clinical trials of biologic agents based on the CASPAR criteria, which do not mandate the presence of enthesitis5; to date, very few trials have listed enthesitis as an inclusion criterion.
Overall, there is a need for studies that assess the effect of treatment on enthesitis and use imaging as an objective measure. Based on a search of ClinicalTrials.gov for studies that required ≥ 1 entheseal site at baseline and used imaging to assess response to treatment, only 2 studies have been designed to date and are currently ongoing.
The ACHILLES trial (NCT02771210)49 is an ongoing phase III, randomized, quadruple-blind study investigating the efficacy of secukinumab in the resolution of Achilles tendon enthesitis, including effects on inflammation as assessed by MRI, in PsA and axial SpA (axSpA). The primary outcome measure is the proportion of patients with resolution of Achilles tendon enthesitis at Week 24 as assessed by the LEI; secondary outcome measures include the percentage of patients with improvement of bone marrow edema as assessed by PsAMRIS. Key inclusion criteria are active PsA or axSpA and MRI-positive heel enthesitis at baseline.
The ULTIMATE trial (NCT02662985)50 is an ongoing phase III, randomized, triple-blind study investigating the sensitivity of US to describe the time course of response to secukinumab in joint synovitis and enthesitis in PsA. The primary outcome measure is the difference between secukinumab and placebo in terms of joint synovitis at Week 12 as assessed by the PDUS Global OMERACT-EULAR Synovitis Score; secondary outcome measures include improvement in enthesitis at Week 12 as assessed by the Spondyloarthritis Research Consortium of Canada Enthesitis Index. Some key inclusion criteria are active PsA and ≥ 1 clinically involved enthesitis site at baseline.
Results of these trials are anticipated to provide much-needed data on the validation of new imaging techniques and scoring scales in the monitoring of enthesitis during clinical trials.
Conclusion
Early diagnosis and treatment of PsA may prevent disease progression and structural damage8. Given that enthesitis is a marker of PsA and an indicator of disease severity, early identification and treatment of enthesitis in patients with PsA is of great importance. Historically, enthesitis has been assessed using a combination of clinical examination and conventional radiography. However, the usefulness of these techniques in the early identification of enthesitis is limited. Newer imaging techniques have since been developed21,30 that allow for direct visualization of the enthesis and related structures and offer the potential to systematically assess enthesitis earlier in the disease course, possibly leading to improved patient outcomes.
Despite this progress, there is currently no gold standard technique to detect enthesitis9. Additionally, more research into the utility of US and MRI for the diagnosis and monitoring of enthesitis in PsA is required. Standardized definitions, imaging techniques, and operator protocols are needed, as are validated scoring systems. Clinical trials that focus on the treatment of enthesitis and use imaging to assess treatment response will allow the efficacy of new therapeutic agents to be assessed and compared more accurately. As technical improvements in imaging are realized, different imaging tools and scoring systems may be preferred for entheses in the lower limbs compared with those in non–weight-bearing, smaller structures. Overall, available data highlight the importance of incorporating imaging modalities in the clinical assessment and management of patients with PsA.
Acknowledgment
Medical writing support was provided by Victoria Kinsley, PhD (SciMentum), and Karen Chinchilla, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corp., East Hanover, New Jersey, in accordance with Good Publication Practice (GPP3) guidelines (www.ismpp.org/gpp3).
Footnotes
This review article was sponsored by Novartis Pharmaceuticals Corp., which manufactures secukinumab.
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- Accepted for publication October 23, 2019.
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Supplementary material accompanies the online version of this article.
