Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trialBMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i4205 (Published 16 August 2016) Cite this as: BMJ 2016;354:i4205
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We read with great interest the paper from Haavardsholm et al. The topic of treat-to-target (T2T) is important for daily clinical practice and could have an impact both on the prognosis and the cost related to the disease. The paper demonstrates that this approach is feasible, with a remission rate of 22% when adding ultrasound (US) to a conventional T2T arm in contrast to a remission rate of 19% in the conventional T2T arm. Furthermore, it clearly shows that US is a reliable imaging modality that can be used in a multicenter study. However, the conclusion of the study, that US have no added value is unexpected and raises some questions to the study design and weighting of the results.
Though it sounds acceptable that US may not be important in assessing treatment effect as long as there are clinical signs of joint activity, the use in monitoring may still be relevant.
In the paper, the high use of corticosteroids at the initiation of treatment in both arms, like the aggressive strategy along with an important number of visits, could explain the scarce difference between the two arms (clinical vs US-guided T2T) in terms of clinical remission. We completely agree on the importance of power Doppler (PD) positivity in the evaluation of US active disease, we regret however, that gray scale synovitis was not considered as an outcome measure (even if this concept is widely accepted). Was gray-scale synovial hypertrophy present in the same extent in both arms both at inclusion and at time of remission? Previous studies have shown that PD positivity is the most important finding but, also gray-scale synovitis is indicative of erosive progression over time (1).
We would also like to point out that in the study two different US machines were used and apparently, a comparability exercise between machines was not performed. This may have determined an impact on scoring inflammatory activity, as differences in Doppler sensitivity may vary between machines (2). We also find the lack of blinding in the study problematic: US examination was performed on every visit in the US arm and only yearly in the clinical arm. It would have been preferable to have both the sonographer and the patient blinded to the treatment arm by having equally amount of US examinations in both arms and a separation between the treating physician and the sonographer, which may be causing a bias.
The two groups (US arm and clinical arm) were not matched as a higher prevalence of female patients was present in the US arm. As female RA patients do not as easily achieve remission as men (3, 4) and this may possibly have had an impact on the results of the study.
Another interesting point is the proportion of swollen joints, which is higher than tender joints in the enrolled patients. We could hypothesize that osteoarthritis may play a role in the results. Mandl et al (5) demonstrated that osteoarthritic joints often are mistaken for swollen joints at the clinical examination, resulting in higher DAS scores, with the risk of patients being in remission but still considered to be active. It is also questionable if it is worth using a very sensitive and reliable (6) imaging modality (like US) and, after all, consider, in the outcomes, only clinical results (US is known not to correlate to DAS scores in patients in clinical remission but may still be showing subclinical synovitis) (7). We are surprised to find such little emphasis on the trend toward significant better results in the US T2T group for structural damage, though the findings are in accordance with previous studies (1, 8-18). Therefore, a longer follow-up could potentially have produced statistically significant differences between groups.
Finally, when looking at the US outcomes, we notice that US T2T arm have significant better results than clinical T2T arm both at 12 and 24 months (especially for the “mean change in US total score” and for the “no PD signal in any joint”). This could justify the use of US in the follow-up of the patients in a daily clinical setting, because of the extensive literature that demonstrates the correlation between the persistence of PD and the progression of the structural damage (1, 8-18), which correlates to worse outcomes in terms of quality of life and function. The latter point is strengthened by the number of papers supporting the importance of PD, and therefore it is surprising that the only publication showing not significant results, is the only reported by the Authors (19).
Though the ARCTIC study is a well conducted study, some issues remain that could have cast further light on the use of US monitoring in RA patients during treatment. It is important to highlight that the produced results are based on very early RA patients (less than 1 year of symptoms duration) and, then, can not be extrapolated to the whole RA patients group.
1. Brown AK, Conaghan PG, Karim Z, et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008;58:2958-67. doi:10.1002/art.23945.
2. Torp-Pedersen S, Christensen R, Szkudlarek M et al. Power and color Doppler ultrasound settings for inflammatory flow: impact on scoring of disease activity in patients with rheumatoid arthritis. Arthritis Rheumatol 2015 Feb;67:386-95.
3. Svensson B, Andersson M, Forslind K, Ajeganova S, Hafström I; BARFOT study group. Persistently active disease is common in patients with rheumatoid arthritis, particularly in women: a long-term inception cohort study. Scand J Rheumatol 2016 Nov;45:448-455.
4. Hamann P, Holland R, Hyrich K et al. Factors Associated with Sustained Remission in Rheumatoid Arthritis in Patients Treated with Anti-Tumour Necrosis Factor (anti-TNF). Arthritis Care Res (Hoboken). 2016 Aug 26. doi: 10.1002/acr.23016. [Epub ahead of print]
5. Mandl P, Balint PV, Brault Y et al. Metrologic properties of ultrasound versus clinical evaluation of synovitis in rheumatoid arthritis: results of a multicenter, randomized study. Arthritis Rheum 2012;64:1272-82.
6. Geng Y, Han J, Deng X, Zhang Z. Presence of power Doppler synovitis in rheumatoid arthritis patients with synthetic and/or biological disease-modifying anti-rheumatic drug-induced clinical remission: experience from a Chinese cohort. Clin Rheumatol 2014;33:1061-6.
7. Wakefield RJ, Gibbon WW, Conaghan PG et al. The value of sonography in the detection of bone erosions in patients with rheumatoid arthritis: a comparison with conventional radiography. Arthritis Rheum 2000;43:2762-70.
8. Wakefield RJ, Gibbon WW, Conaghan PG et al. The value of sonography in the detection of bone erosions in patients with rheumatoid arthritis: a comparison with conventional radiography. Arthritis Rheum 2000;43:2762-70.
9. Baillet A, Gaujoux-Viala C, Mouterde G et al. Comparison of the efficacy of sonography, magnetic resonance imaging and conventional radiography for the detection of bone erosions in rheumatoid arthritis patients: a systematic review and meta-analysis. Rheumatology (Oxford) 2011;50:1137-47. doi: 10.1093/rheumatology/keq437.
10. Taylor PC, Steuer A, Gruber J et al. Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Arthritis Rheum 2004;50:1107-16.
11. Naredo E, Collado P, Cruz A et al. Longitudinal power Doppler ultrasonographic assessment of joint inflammatory activity in early rheumatoid arthritis: predictive value in disease activity and radiologic progression. Arthritis Rheum 2007;57:116-24.
12. Macchioni P, Magnani M, Mulè R et al. Ultrasonographic predictors for the development of joint damage in rheumatoid arthritis patients: a single joint prospective study. Clin Exp Rheumatol 2013;31:8-17.
13. Sant'Ana Petterle G, Natour J, Rodrigues da Luz K et al. Usefulness of US to show subclinical joint abnormalities in asymptomatic feet of RA patients compared to healthy controls. Clin Exp Rheumatol 2013;31:904-12.
14. Brown AK, Quinn MA, Karim Z et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006;54:3761-73.
15. Nguyen H, Ruyssen-Witrand A, Gandjbakhch F, Constantin A, Foltz V, Cantagrel A. Prevalence of ultrasound-detected residual synovitis and risk of relapse and structural progression in rheumatoid arthritis patients in clinical remission: a systematic review and meta-analysis. Rheumatology (Oxford) 2014;53:2110-8. doi: 10.1093/rheumatology/keu217.
16. Brown AK, Conaghan PG, Karim Z, et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008;58:2958-67. doi:10.1002/art.23945.
17. Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G. Clinical and ultrasonographic remission determines different chances of relapse in early and long standing rheumatoid arthritis. Ann Rheum Dis 2011;70:172-5. doi:10.1136/ard.2010.129924.
18. Scirè CA, Montecucco C, Codullo V, Epis O, Todoerti M, Caporali R. Ultrasonographic evaluation of joint involvement in early rheumatoid arthritis in clinical remission: power Doppler signal predicts short-term relapse. Rheumatology (Oxford) 2009;48:1092-7. doi:10.1093/rheumatology/kep171.
19. Gärtner M, Alasti F, Supp G, Mandl P, Smolen JS, Aletaha D. Persistence of subclinical sonographic joint activity in rheumatoid arthritis in sustained clinical remission. Ann Rheum Dis 2015;74:2050-3. doi:10.1136/annrheumdis-2014-207212.
Competing interests: No competing interests
Haavardsholm et al must be congratulated on their study of ultrasound (US) in rheumatoid arthritis. The >200 patients received extraordinary attention to therapeutic detail, with great efficacy in both arms, and under the circumstances of this study US examination did not improve outcomes. However, this strategy trial targeting clinical remission did not test the hypothesis that reducing US power Doppler (PD) reduces damage. This was because PD was reduced equally in the two arms (-9.0 vs -9.6 US vs conventional tight control at 24 months) and in both arms most patients ended up having no PD. So the question is not why US failed? But rather why conventional tight control did so well, reducing PD to a level not previously achieved?
There are a number of reasons for this. First, it was an extraordinary study with nine visits in the first year and numerous escalations of therapy. Second, a large amount of steroids were used for escalation with an average of five injections even in the conventional arm. In addition all patients received oral steroid (15mgs) at onset, these steroids would have minimised differences between arms in an early population with relatively low disease activity. Given the frequent visits and the very frequent escalations of therapy US examinations were largely redundant, as therapy was being escalated for clinical grounds in 75% of the cases anyway. Furthermore, an extremely rigorous endpoint of clinical remission, swollen joints and non-progression of radiographic damage was used. Two of the three primary endpoints were identical to the treatment target in the conventional arm and treatment was adjusted on the basis of these components, resulting in a potentially biased design (in fact the other end-point, radiographic progression, was improved in US arm, p<0.05) probably explained by the higher number of joints with no PD. Finally, there was unequal sex distribution between the 2 groups, with the US arm having 50% more females, who have a worse prognosis.
For patients in a stable state it is recommended to use US when escalation of therapy would not normally be indicated2. Under such circumstances, if sub-clinical synovitis is found, then further therapy may be indicated. The ARCTIC study tested a very different approach of undertaking a tightly (every month in the first 4 months and then bimonthly) clinical or clinical + US evaluation at each visit with the result that the vast majority of US scans had no additional impact on therapy. Only by US resulting in a change of therapy, which would not otherwise have occurred, would benefit have been demonstrated. Thus ARCTIC was not capable of determining whether treating sub-clinical disease (found on US) produces improvement in the long-term outcome.
The most important finding from ARCTIC is that rheumatoid arthritis treated with exceptional care (in one of the wealthiest countries which can afford such intensive therapy) very low levels of PD for the first time can be achieved; with “most patients in both groups having no Power Doppler”. However, to conclude “isolated sub-clinical inflammation, in the absence of clinically detectable disease has minimal clinical importance” is not possible from the data in this paper.
Unfortunately, most patients in clinical remission, treated outside such a study, continue to have sub-clinical synovitis detected by US3, which has been shown to be predictive of subsequent damage and flare. For these patients and for many other indications US still has an important role.
Paul Emery, MA MD FRCP FMedSci
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust
Kei Ikeda, MD, PhD
Chiba University Hospital, Chiba, Japan
Maria-Antonietta D’Agostino, MD,PhD
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds
Hôpital Ambroise Paré, Rheumatology Department
INSERM U1173, Laboratoire d’Excellence INFLAMEX, UFR Simone Veil, Versailles-Saint-Quentin University, Saint-Quentin en Yvelines, France
Professor Emery’s research is supported by the National Institute for Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
1 Haavardsholm EA, Aga A-B, Olsen IC et al. Ultrasound in the management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial. BMJ 2016;354:i4205.
2 D’Agostino MA, Terslev L, Wakefield RJ et al. Novel Algorithms for the Pragmatic Use of Ultrasound in the Management of Rheumatoid Arthritis Patients: from Diagnosis to Remission Ann Rheum Dis 2016 Aug 23. pii: annrheumdis-2016-209646.
3 Saleem B, Brown AK, Quinn M, et al. Can flare be predicted in DMARD treated RA patients in remission, and is it important? A cohort study. Ann Rheum Dis. 2012;71:1316-21
Competing interests: Paul Emery has undertaken clinical trials and provided expert advice to Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz and Lilly