Does ACPA-negative RA consist of subgroups related to sustained DMARD-free remission and serological markers at disease presentation? Comment on article by Boeters DM et al.

Letter to the Editor

We read with interest the article by Boeters DM et al. [1]. We would like to clarify the significant findings and suggest further research needed to validate the novel conclusion. In ACPA-negative patients, 1 sustained DMARD-free remission (SDFR) occurred over 5 years follow-up in 17 (6%) with baseline low (< 30) MBDA score vs approximately 50% remissions in both moderate (30–44) and high (> 44) MBDA score patients ([1], Fig. 1). All ACPA-positive RA patients had low percentages of SDFR and no difference was found by baseline MBDA score category [1]. Percentages of 3 MBDA categories did not differ (p = 0.470) between the ACPA-positive and ACPA-negative groups [1].

SDFR was recently reported by ACPA-negative vs ACPA-positive patients in the total Leiden early arthritis cohort (1993–2016; n = 1296) [2], from which the Boeters et al. study [1] was the most recent inclusion subgroup (2011–2016). In the total inclusion period (1993–2011), SDFR occurred between 5 and 15% in ACPA-positive RA vs 40 to 50% in the ACPA-negative RA [2], as in Boeters et al. [1].

Unexpectedly, in multivariate analyses ([1], Table 2), the 95 ACPA-negative RA patients with high (> 44) baseline scores had greater DMARD-free remission than the 17 reference patients with low (< 30) MBDA scores (p = 0.041). If MBDA were truly a marker of disease activity, one might expect low rather than high MBDA to predict SDFR. Alternatively, if ACPA-negative RA does consist of subgroups [1], its documentation will require further serological study in separate cohorts [2, 3] or search for genetic markers [3]. Confounding variables should be excluded, possibly clinical features related to age at onset, which was found to be a significant (p = 0.036) predictor of SDFR ([1], Table 2) and other disease variables not studied. Is it conceivable that this anomaly [1] is due to chance occurrence in a small sample size study leading to an incorrect conclusion, especially when borderline (p = 0.041) statistical correlation is found [1]?

A critical review of the value of multibiomarker disease activity score to predict remission in RA was recently published [4]. The challenging question is whether or not baseline MBDA (or serological markers) are being overinterpreted or overstated with respect to outcomes (or disease subgroups) was critically analyzed [4].