Gray-Scale US Predicts RA Damage, but Clinical Use Unclear

Joint damage caused by rheumatoid arthritis (RA) may progress even in treat-to-target (T2T) cases in clinical remission. The finding has stimulated interest in the use of joint imaging as an early warning tool. This might be particularly useful for monitoring patients taking biological disease-modifying antirheumatic drugs (bDMARDs), in whom uncoupling of inflammation and structural damage may complicate treatment decisions.

Burkhard Möller, MD, senior physician, Inselspital, University Clinic for Rheumatology, Immunology and Allergy, University Hospital, Bern, Switzerland, and colleagues report their findings in an article published online October 19 in Rheumatology.

Swiss RA register data on joint damage predictions from a single baseline ultrasound showed that joint damage progression (∆Xray) at 3 years was most accurately predicted by gray-scale ultrasound (GSUS) or CombUS scores (GSUS plus PDUS) exceeding 20% to 30% of the maximum synovitis grading. The researchers defined significant radiographic progression as a 3.5% change in Ratinger score.

Adding PDUS to GSUS to produce a CombUS score, as recommended in recent EULAR-OMERACT guidance, was not significantly better than using GSUS alone.

A single GSUS reading contained more information than any clinical composition (DAS28, CDAI, etc) of subjective and objective parameters for predicting joint damage progression, Möller told Medscape Medical News.

"This finding may at a first glance be counterintuitive to the primacy of clinical measures in T2T approach. However, T2T requires repeated assessments, but their frequency currently is arbitrary," he said. "This was the reason to limit this analysis to only a single assessment. We do not know how repeated GSUS or clinical composite measures will perform in predicting joint damage progression," he explained.

According to the authors, "Despite the many significant associations of US-detected synovitis and ∆Xray, the formal diagnostic performance of every single US index test at baseline was not satisfactory. However, as we could not observe a stronger association between ∆Xray and any of the tested clinical disease activity measures in this study, we consider this a practically relevant finding."

Möller added, "I conclude from our observation that any appearance of synovial hyperplasia beyond a certain cutoff might be critical to the maintenance of joint structured and should be targeted."

Other experts were more cautious, including Tamotsu Kamishima, MD, PhD, whose group has studied synovial changes and joint damage progression in RA patients in whom there was low disease activity. Kamishima is from the Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

He told Medscape Medical News, "I do not believe clinicians should be using gray-scale US to monitor synovitis in RA patients. These findings should not affect treatment decisions.

"I understand the authors' point that the real-life setting of this study with many examiners, long observation time, and the different equipment in use make this result practically relevant," Kamishima added. "However, when you look at Table 1, Ratingen x-ray hands score was 6 (2 – 13), vs 13 (3 – 22) for CombUS < 15/54 and CombUS ≥ 15/54, respectively. Although there was a statistically significant difference between them (P = .0044), there should be considerable overlap between them," he explained.

This overlap could be even more problematic in view of the time and effort required to acquire/score/report for ultrasonographic examination in each case, Kamishima said. However, according to Möller, for those with sufficient experience, GSUS testing takes about 10 minutes, depending on the level of joint damage and on the patient's limitations in movement while undressing.

Study Assessed Three Ultrasound Methods

The nested cohort study included all patients for whom sequential hand radiographs from their first US assessment were available. The researchers analyzed semiquantitative GSUS, PDUS, and CombUS assessments of both wrists and 16 finger joints (maximum, 54 points) at their upper limit of normal, their 50th, 75th, or 87.5th percentiles for the progression of joint damage.

The multivariate analysis adjusted for clinical disease activity measures at baseline, the use of biological DMARDs, and other confounders. There were 287 patients in the GSUS group, 259 patients in the PDUS group, and 250 patients with CombUS composite scores.

The authors note that adding PDUS to the GSUS raised CombUS scores by just one point. Möller said he was surprised that the performance of PDUS in predicting joint damage progression was poor. "Based on my clinical experience, PDUS is more fluctuant over time than GSUS. Consequently, was the long time between US and follow-up x-ray probably more critical for PDUS than GSUS? Moreover, PDUS is less robust to technical flaws than GSUS, which might especially be relevant in our real-life study," he said.

Kamishima commented on the "relatively low performance of power Doppler examination. In my opinion, this is due to the fact that the machine and evaluation system utilized are suboptimal for this type of study," he said.

bDMARDs Used by Many Patients

At baseline, 44% of patients were taking bDMARDs; an additional 35% started taking bDMARDs during follow-up. "Treatment adaptations were not protocol guided, but bDMARDs were more often initiated in patients with clinical and imaging indicators of high disease activity. Furthermore, bDMARDs were more frequently discontinued in subjects with low disease activity indicators," the authors explain.

At a median follow-up of 35 months, roughly one quarter of patients in each group experienced radiographic joint damage progression. The cutoff scores for baseline ultrasound with the greatest specificity for predicting radiographic progression for RA patients treated either with conventional DMARDs or with bDMARDs were ≥14/54 for GSUS and ≥15/54 for CombUS.

"Higher levels of GSUS and CombUS are associated with the development of erosions," the researchers write. "GSUS appears to be an essential component of synovitis assessment and an independent predictor of joint damage progression in patients on biological DMARDS."

Single-Joint Gray-Scale US Predicted Progression of RA Damage

The authors conclude, "This study shows for the first time in a large registry the value of a single joint US for the risk assessment of radiographic joint damage on a subsequent median 3-year period." They warn that "quite low grades of synovial pathologies" can be important for structural outcomes for patients with RA.

Limitations of this observational study included the fact that there was no protocol for the follow-up of patients, there was large variation in the amount of time between follow-up radiographs, medical treatment was not prescribed per protocol, and it was not possible to track individual changes in medical treatment back to disease activity.

The study was supported by unrestricted research grants from AbbVie Switzerland and Bristol-Myers Squibb Switzerland. The authors and Kamishima have disclosed no relevant financial relationships.

Rheumatology. Published online October 29, 2019. Full text

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