Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial

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