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We read the editorial by Filippucci et al., entitled "Ultrasound definition of enthesitis in spondyloarthritis and psoriatic arthritis: arrival or starting point?" with great interest. The authors eloquently discuss the challenges with the existing scoring methods and propose solutions (1). We would like to raise additional points that we believe are necessary to improve the assessment of enthesitis using ultrasound.
Before the introduction of ultrasound to the field, enthesitis was determined as present or absent, based on the physical exam. Therefore, only prevalence could be compared between patient groups. Ultrasound allows precise phenotyping of the entheseal changes. The ability to accurately characterize anatomical changes within the entheseal soft tissue and on the surface of the bone, detect abnormal vascularisation and further categorize the two opposite bony changes (erosion vs new bone formation) brought a different perspective on the understanding of enthesitis. Despite some similarities between psoriatic arthritis (PsA) and other spondyloarthritis (SpA) subtypes, clear distinctions also exist (2). From the enthesitis perspective, patients with PsA have larger enthesophytes (bony spurs) at the entheseal insertions than ankylosing spondylitis (AS), despite similar levels of sonographic inflammation (3). Supporting that observation, psoriasis is shown to be an independent risk factor for enthesophytes with Axial SpA (4). Similar findings have lo...
Before the introduction of ultrasound to the field, enthesitis was determined as present or absent, based on the physical exam. Therefore, only prevalence could be compared between patient groups. Ultrasound allows precise phenotyping of the entheseal changes. The ability to accurately characterize anatomical changes within the entheseal soft tissue and on the surface of the bone, detect abnormal vascularisation and further categorize the two opposite bony changes (erosion vs new bone formation) brought a different perspective on the understanding of enthesitis. Despite some similarities between psoriatic arthritis (PsA) and other spondyloarthritis (SpA) subtypes, clear distinctions also exist (2). From the enthesitis perspective, patients with PsA have larger enthesophytes (bony spurs) at the entheseal insertions than ankylosing spondylitis (AS), despite similar levels of sonographic inflammation (3). Supporting that observation, psoriasis is shown to be an independent risk factor for enthesophytes with Axial SpA (4). Similar findings have long been demonstrated in the spine, with bulkier syndesmophytes of axial PsA patients compared to AS (2). One potential explanation for these differences is the abnormal response of psoriasis patients to trauma which has been well recognized at the skin level. The exacerbated response in the deeper tissues in PsA is hypothesized to be the reflection of the same process, known as the Deep Koebner phenomenon (5, 6). Therefore, we believe that a tool to diagnose enthesitis in PsA may differ from other SpA subtypes. More specifically, when the purpose is to diagnose patients early, a scoring method that is developed to screen for enthesitis in SpA other than PsA, may not need to include the enthesophytes. However, given how the large enthesophytes differentiate PsA from other subtypes, the enthesophytes may be more valuable within a diagnostic tool developed for PsA. Although enthesophytes can separate the groups, they do not constitute an element of disease activity, whereas other lesions such as hypoechogenicity or Doppler may be used for monitoring change. Hence, there may be differences between the sonographic tools that are developed for diagnosis vs therapy monitoring. Outcome Measures in Rheumatology (OMERACT) definitions inherently are not for diagnostic use but are for longitudinal use to follow outcomes after interventions and are designed using OMERACT metrics. The authors of this manuscript suggest that a targeted data-driven approach should be undertaken in creating diagnostic ultrasound instruments. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) / ultrasound group is currently conducting an international multicenter study (DUET) (Diagnostic Ultrasound Enthesitis Tool) to obtain a feasible, reliable and accurate tool to differentiate PsA from its mimics for earlier diagnosis (7). Using statistical modelling, the group will identify the optimal combination of entheseal sites and sonographic lesions that distinguish PsA from controls with minimal influence by confounding factors.
Another critical aspect raised by Filippucci et al. is the importance of the small entheses in SpA. Ultrasound is an operator and machine-dependent modality, and the ability of a sonographer to accurately evaluate the large entheses usually occurs earlier than the small entheses in the learning curve. Hence, the earlier studies on enthesitis focused on the large enthesis, leading to the existing scoring methods (8). We agree with Filippucci et al. that the large entheses are more exposed to the impact of biomechanical stress, leading to entheseal alterations in healthy people (9). Therefore, one may consider scanning the small entheses for being less impacted by "physiological responses" that are confounded by age, BMI, physical activity and gender. On the other hand, if SpA (especially PsA) patients respond more aggressively to the same biomechanical forces than the healthy people within the large entheses, it may be more likely to find features that can differentiate the disease state from health. Despite the relatively high prevalence of entheseal ultrasound findings in healthy people, studies found a significant difference between SpA and healthy controls at a group level, especially if matched BMI, age, and gender (10). Therefore, we may need to revisit our thresholds to determine the normal range in entheseal ultrasound and consider the patient-related factors when determining those considered "normal" (similar to the growth charts that define the "normal" with the percentiles given separately for age and sex).
On the other hand, we fully agree with Filippucci et al. that it is time to focus on the small entheses to improve our patients' care. Multiple studies published in the last five years have demonstrated the significance of not only the small entheses but also the extraarticular structures in the hands (e.g. paratenon of the extensor tendon, subcutaneous tissue, pulleys and nails). We also would like to emphasize that most of the data within the field of small enthesis are in PsA, not in other subtypes of SpA, which is likely to be due to the nature of the diseases (small joints affliction is more prevalent in PsA). Therefore, understanding the importance of small enthesis and how that can be valuable for early diagnosis requires doing research in SpA subtypes separately, without lumping them. The GRAPPA ultrasound group is also working on evaluating the musculoskeletal structures in the hands beyond the joints, including the small entheses, merging the knowledge and expertise in this area.
To conclude, we believe we are neither at the arrival nor starting point for the ultrasound of the enthesis. The progress in this field has significantly improved our understanding of the role of enthesitis in the pathogenesis of SpA. With significant efforts from the GRAPPA and OMERACT ultrasound groups, as well as individual experts running well-designed studies globally, we have reasons to be optimistic that the finish line, having standardized screening tools for enthesitis, is on the horizon.
1. Filippucci E, Smerilli G, Di Matteo A, Grassi W. Ultrasound definition of enthesitis in spondyloarthritis and psoriatic arthritis: arrival or starting point? Ann Rheum Dis. 2021.
2. Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol. 2018;14(6):363-71.
3. Arslan Alhussain F, Kasapoglu Gunal E, Kurum E, Bakirci S, Ozturk AB, McGonagle D, et al. Greater magnitude of entheseal microdamage and repair in psoriatic arthritis compared with ankylosing spondylitis on ultrasound. Rheumatology (Oxford). 2019;58(2):299-303.
4. Solmaz D, Bakirci S, Jibri Z, Sampaio M, Karsh J, Aydin SZ. Psoriasis is an independent risk factor for entheseal damage in axial spondyloarthritis. Semin Arthritis Rheum. 2020;50(1):42-7.
5. Pattison E, Harrison BJ, Griffiths CE, Silman AJ, Bruce IN. Environmental risk factors for the development of psoriatic arthritis: results from a case-control study. Ann Rheum Dis. 2008;67(5):672-6.
6. Tinazzi I, McGonagle D, Aydin SZ, Chessa D, Marchetta A, Macchioni P. 'Deep Koebner' phenomenon of the flexor tendon-associated accessory pulleys as a novel factor in tenosynovitis and dactylitis in psoriatic arthritis. Ann Rheum Dis. 2018;77(6):922-5.
7. Eder L, Kaeley GS, Aydin SZ. Development and Validation of a Sonographic Enthesitis Instrument in Psoriatic Arthritis: The GRAPPA Diagnostic Ultrasound Enthesitis Tool (DUET) Project. J Rheumatol Suppl. 2020;96:50-2.
8. Elalouf O, Bakirci Ureyen S, Touma Z, Anderson M, Kaeley GS, Aydin SZ, et al. Psoriatic Arthritis Sonographic Enthesitis Instruments: A Systematic Review of the Literature. J Rheumatol. 2019;46(1):43-56.
9. Bakirci S, Solmaz D, Stephenson W, Eder L, Roth J, Aydin SZ. Entheseal Changes in Response to Age, Body Mass Index, and Physical Activity: An Ultrasound Study in Healthy People. J Rheumatol. 2020;47(7):968-72.
10. Kaeley GS. Visualization of Enthesitis by Ultrasound: a Key Diagnostic Tool in Spondyloarthropathy Diagnosis and Management. Curr Rheumatol Rep. 2020;22(9):48.