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Abstract
Ultrasound (US) unquestionably improves many aspects of rheumatoid arthritis (RA) diagnosis and management, but no consensus has been reached regarding the optimal US methodology that should be used, and high levels of standardisation have not yet been attained. Current evidence from two randomised controlled trials does not support the US in directing treatment decisions. A return to the endorsement of clinical assessment and the adoption of T2T strategies aiming at ACR/EULAR remission still represent the standard of care for RA and should be pursued through appropriate educational programmes. Thus, for now, the major application of sonography in arthritis should have a focus on diagnostic and especially differential diagnostic aspects.
- rheumatoid arthritis
- ultrasonography
- disease activity score
- remission
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In recent years, the scientific literature has produced an increasing number of publications supporting the potential advantages of integrating musculoskeletal imaging, especially ultrasound (US), into the management of rheumatoid arthritis (RA).1–3 The added value of US has been advocated at all levels of the disease stages4: from predicting diagnosis,1 to supporting the diagnostic and classification process,5 guiding treatment choices and response,6 predicting structural damage and flares,7 8 and influencing the concept and management of remission and treatment tapering.9 10 US has been shown to be superior to clinical assessment in detecting inflammation by assessing the presence of the most important elementary lesions in RA: synovial hypertrophy (SH), synovial effusion (SE) and Power Doppler activity (PD).2 Nevertheless, some recent evidence has unexpectedly highlighted major pitfalls of the most widespread imaging tool in the field of RA.
First of all, it is not clear what SH (grey scale) or a PD signal really mean; it has been shown repeatedly that SH can also represent a residue of past synovitis, and therefore, it does not appear to be a reliable tool to assess ongoing inflammation.11 The meaning of pathological findings can change according to the age group being assessed; it has been reported that synovial abnormalities are frequent in clinically inactive juvenile idiopathic arthritis and do not predict a flare of synovitis.12 Moreover, PD signals have not consistently been found to be associated with histopathological findings of inflammation, with some discordant results,13 14 suggesting that the interpretation of sonographic findings in RA is unreliable or, at best, equivocal. Second, even the European League Against Rheumatism (EULAR) recommendations for the use of imaging of the joints in the clinical management of RA15 identified the lack of strong evidence to support the role of US and the urgent need for standardisation and dedicated trials. US was included in most of the recommended points, however, with vague and quite general indications on its use such as ‘US may be used’, and with a low level of evidence. No specific details on which joints to assess, how often and on the pathological findings to look for could be given.
But perhaps, we should go one step backwards and restart by looking at healthy individuals. To date, there is still no clear definition of what can be considered a normal finding of musculoskeletal US. It has been known since more than a decade that >10% of the joints of healthy individuals are PD-positive; it has recently been shown that 88% of 207 healthy subjects presented at least one joint with US abnormal findings: signs of SE in 52% of them, presence of SH in 48% (with or without PD positivity); in 64 subjects, SH was associated with SE and in eight cases with PD.16 Erosions can also be found in healthy subjects,16 a finding that has been recently corroborated by MRI.17 Given the fact that single US abnormalities may not represent pathological findings, it is the combination of different pieces of information such as the age of the patient, the grade of detected abnormality and the number of joints affected that may be more useful in the interpretation of the significance of US appearances.
In 2005, the Outcome Measures in Rheumatology (OMERACT) Ultrasound group18 made the first attempt to provide consensus definitions of ultrasonographic pathology in inflammatory arthritis. Nevertheless, subsequent systematic reviews of the literature to assess the scoring systems for synovitis, tendon lesions and erosions applying the OMERACT filter demonstrated the absolute lack of standardisation and agreement concerning the use of US in RA,2 19 20 including but not limited to number and type of joints to be assessed and comparators for construct validity (clinical examination, laboratory findings or other imaging modalities). The development of standardised procedures is further complicated by the variability introduced by differences in machine characteristics and resolutions, settings, transducers and presets, particularly when assessing PD.19
In this context of uncertainty, two very recent trials tried to fill the gap by assessing the role of US over conventional clinical approaches for achieving clinical remission under a treat to target (T2T) tight control approach: the ‘Targeting Synovitis in Early Rheumatoid Arthritis’ (TaSER) and the ‘Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical Tight Control regimen’ (ARCTIC).21 22 Both trials set out to test the hypothesis that ‘incorporating muscoskeleteal ultrasound (MSUS) disease activity assessment into a T2T strategy would produce superior clinical and imaging outcomes compared with a strategy driven by a composite disease activity score’.23 Both trials concluded that the routine, systematic use of US to inform on treatment decisions does not add to clinical management of RA in terms of clinical or imaging outcomes. Thus, when using a T2T strategy aimed at clinical remission or even low disease activity, the two prospective clinical trials demonstrated that following patients using sonography is not needed20 21 and may be both time consuming and economically unsound.22 While providing some disappointing results on the adjunctive role of US, the two trials reinforced the evidence on the really good outcomes achieved by following the clinical T2T strategy. Even if there are certainly some limitations of these studies, as mentioned in a recent viewpoint article,24 we should not forget that, despite having been known long before,23 the methodology and design of at least one of these trials were criticised only after the final results questioning the advantage of targeting sonographic remission had been published.
As a matter of fact, the recently published 2016 EULAR recommendations for the management of early arthritis stated that both for detecting arthritis and for monitoring disease activity, the role of US is still to be fully elucidated.25
It is well known that applying the T2T and tight control paradigm ensures better long-term outcomes in terms of remission rates and duration, halting of structural progression and prevention of functional and work disability, regardless of the therapeutic strategy.26–28 Indeed, patients who achieve stringent clinical remission have significantly less damage progression, even on methotrexate monotherapy,29–31 and experience normalisation of physical function32—so how much better than being associated with non-progression of damage and normal function can sonographic remission be? Indeed, the adoption of more stringent targets such as the American College of Rheumatology (ACR)/EULAR criteria for remission (both the index-based and Boolean definitions) has been strongly associated with the achievement of the best outcomes, including (notably) absence of sonographic disease activity.33–35 While low disease activity is an alternative treatment target,26 the clinical, functional and radiographical outcomes are nevertheless worse than in stringent remission.36–38
Nonetheless, we do acknowledge that US assessments in the routine management of RA need to be further improved and clinical assessment warrants a higher degree of standardisation. Indeed, while the vast majority of rheumatologists agree (in theory) with the principles of the T2T strategy and the scientific value of more stringent remission criteria, the application in clinical practice is still suboptimal, and the choice of the target often deviates from the recommended definitions.39 40
In routine clinical practice, the majority of us still apply DAS28-based definition of remission, conscious of the significant level of residual disease activity allowed by these measures. This happens despite the availability of more stringent and easy to apply disease activity measures such as the Clinical Disease Activity Index41 that can be quickly calculated without the need for a calculator or inflammatory markers results. Should we then ‘stop fooling ourselves’ (as suggested by Boers42) at least when designing clinical trials or reviewing submitted manuscripts still adopting definitions of remission different from ACR/EULAR definitions?
In conclusion, US unquestionably improves many aspects of disease diagnosis and management, but no consensus has been reached regarding the optimal US methodology that should be used, and high levels of standardisation have not yet been attained. Current evidence from randomised controlled trials does not support the US in directing treatment decisions. A return to the endorsement of clinical assessment and the adoption of T2T strategies aiming at ACR/EULAR remission still represent the standard of care for RA and should be pursued through appropriate educational programmes. Thus, for now, the major application of sonography in arthritis should have a focus on diagnostic and especially differential diagnostic aspects—there it has been and continues to be an extremely powerful pillar.43 44
References
Footnotes
Contributors Both the authors gave substantial contributions to the conception of the paper as well as drafting the paper and revising it critically for important intellectual content. They gave final approval of the version to be submitted.
Disclaimer JS has received grants for his institution from Abbvie, Astra-Zeneca, Janssen, Lilly, MSD, Pfizer, Roche and has provided expert advice to and/or had speaking engagements for Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. RC has provided expert advice to and/or had speaking engagements for Abbvie, BMS, Celgene, Celltrion, Janssen, Lilly, MSD, Mundipharma, Novartis-Sandoz, Pfizer, Roche, Sanofi, UCB.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.