Does Systematic Ultrasound Evaluation of Early RA Lead to Overtreatment?

Data from a randomized interventional clinical trial (ClinicalTrials.gov Identifier NCT01205854) suggest that no clinical benefit is gained when ultrasound is used to guide treatment decisions in early rheumatoid arthritis (RA).  Measured outcomes were not improved with increased resource utilization allocated to performing ultrasounds as part of a treatment strategy in RA.

Recent emphasis on the importance of early, goal-directed therapy with the aim of achieving RA disease remission has encouraged clinicians and researchers to evaluate new diagnostic modalities to evaluate structural joint damage. Ultrasound has been increasingly used to assess both joint synovitis morphology and synovial vascularity, and has been suggested as a sensitive diagnostic tool to monitor RA disease inflammation.

Researchers in Norway designed a 24-month open label, multi-center, randomized clinical trial to systematically determine whether the use of ultrasound to target RA pharmacotherapy led to improvements in sustained disease remission and prevention of further destruction of joint damage. The primary objective of the ARCTIC trial (Aiming for Remission in rheumatoid arthritis: a randomized trial examining the benefit of ultrasound in a Clinical TIght Control regimen) was to compare patients who had ultrasonography incorporated into a comprehensive treatment strategy with those receiving standard of care treatment.

Patients fulfilling the American College of Rheumatology (ACR) or European League Against Rheumatism (EULAR) criteria for RA who were previously naïve to disease-modifying antirheumatic drugs (DMARDs) and had a disease duration of less than 2 years were eligible for inclusion into ARCTIC.  Patients were randomized 1:1 to receive either “conventional tight control” therapy or “ultrasound tight control therapy,” with ultrasound assessments performed at every clinic assessment according to the 32 joint scoring system. 

The ultrasound tight control group had RA pharmacotherapy that aimed for ultrasound imaging-defined remission, with no ultrasound power Doppler signal present in any of the assessed joints. All patients were assessed at baseline and then at months 1-4; 6, 8, 10, 12, 14, 16, 20, and 24. Bilateral radiographs of the hands, wrists, and feet  were taken at months 0, 3, 6, 12, 16, and 24 and read by 2 blinded readers according to van der Heijde modified Sharp score and joint space narrowing.

Disease Activity Score (DAS) <1.6 with the absence of swollen joints on physical exam was used to define clinical remission. A treatment escalation algorithm was used to guide treatment, with the initial methotrexate (MTX) dose of 15 mg/week being titrated to 20 mg/ week within the first 5 weeks of treatment, with the option to titrate to 25 mg/week and/or add triple synthetic DMARD therapy (MTX, sulfasalazine, hydroxychloroquine) in addition to a prednisolone taper from 15 mg to discontinuation. 

Researchers selected proportion of patients fulfilling the following criteria as the primary endpoint of the trial: sustained clinical remission ( DAS<1.6 at 16, 20, and 24 months), absence of swollen joints at 16, 20, and 24 months, and lack of radiographic progression (<0.5 units change in van der Heijde modified Sharp score between 16 and 24 months). DAS-defined remission, Simplified Disease Activity Index scores of  ≤3.3, ACR core set outcome variables, and the fatigue subscale of the visual analog scale were used as measures of secondary endpoints.

A total of 238 patients were accepted into the ARCTIC trials, with 118 of these patients randomized to the ultrasound tight control treatment group (104 eventually completing the trial) and 112 patients randomized to the conventional tight control treatment strategy (100 eventually completing the trial). 

Researchers found that between months 16 and 24, the ultrasound tight control group did not have improved rates of sustained, or improvements in number of swollen joint counts. In the ultrasound-randomized treatment strategy, 26 patients (22%) out of the 118 patients achieved disease control as predefined by the primary endpoint as compared to 21 (19%) of the 112 analyzed patients in the clinical tight control arm (mean difference 3.3%, 95% confidence interval [CI] 7.1% to 13.7%).

At both 12- and 24-months post treatment strategy randomization, no significant differences in DAS remission were found between the 2 treatment groups.

The 24-month change in radiographic joint damage quantified by the total van der Heijde modified Sharp score was also not statistically different between the 2 groups of patients. Similar frequencies of adverse effects were reported in both treatment groups.

These results suggest that despite using a more-targeted treatment strategy using ultrasound in one treatment group, most patients were able to achieve no power Doppler activity in any joint at 2 years post-treatment initiation regardless of treatment group assignment.

“A possible explanation may be that isolated subclinical inflammation in the absence of clinically detectable disease activity has minimal clinical importance, making direct visualization of power Doppler activity unnecessary,” the authors wrote. “We found a trend towards a difference in progression of joint damage, and we do not know whether a longer follow-up period would have shown a benefit of the ultrasound strategy.” 

Summary and Clinical Applicability

A treat-to-target approach using tight ultrasound goals was not found to improve disease activity, radiographic joint damage, or physical function. 

“Although we did not aim to [analyze] cost effectiveness data, the lack of gain in benefits and the increased costs, time consumption, and use of biologic drugs associated with the ultrasound tight control regimen would yield negative cost-benefit ratios,” the study researchers concluded. 

Limitations and Disclosures

• Introduction of possible treatment bias in the open label design of the study, with primary endpoints not being blinded

The NCT01205854 clinical trial was funded by investigator-initiated research grants from AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, and Roche Norway.  The authors report multiple disclosures. Please refer to the study full text for all competing interests.