In this study, we demonstrated that the ROM serum level at 12 weeks in the treatment with BAs was a useful biomarker for predicting the 52-week remission for CDAI, SDAI, and Boolean standards. The HAQ at 12 weeks was also a predictor for the 52-week remission. The AUC values of ROM for the CDAI-remission and SDAI- or Boolean-remission were 0.696 and 0.737, respectively, both of which were moderately accurate; those of HAQ were 0.743 and 0.712, respectively, which were almost equivalent to those of ROM. The sensitivity for the CDAI-remission and SDAI- or Boolean-remission were 50.0% and 52.2%, respectively, although their specificity was over 90%. Considering these results, at present, ROM may not be a highly accurate predictor for the 52-week remission for CDAI, SDAI and Boolean standards. However, CRP and MMP-3, which are biomarkers used to monitor disease activity and joint damage progression in a routine clinical practice, were not identified as predictors for the 52-week remission in a logistic regression analysis. These results suggest that ROM is at least superior to CRP and MMP-3 in terms of predicting future remission.
It seems important to determine the appropriate time point during treatment for predicting 52-week remission. In addition to 12 weeks, we investigated whether the ROM serum level at baseline and at 4 weeks could predict 52-week remission in a logistic regression analysis, but we could not find significant factors (data not shown). Therefore, we decided that 12 weeks was the appropriate time point to measure ROM serum levels for predicting 52-week remission. The finding that the ROM level at 12 weeks can predict the 52-week remission for CDAI, SDAI and Boolean standards could make ROM a useful biomarker for monitoring current treatment strategies relatively early.
Previous studies have demonstrated that the baseline HAQ was associated with remission after treatment. Quintana-Duque et al showed that a lower HAQ-disability index (DI) score and absence of autoantibodies were predictive of remission [10]. Hoshi et al showed that the baseline Japanese version of HAQ was a negative predictor of Boolean-based remission in patients treated with tocilizumab [11]. Pomirleanu et al showed that initial DAS28-ESR, HAQ-DI, CRP, rheumatoid factor (RF), and anti-citrullinated protein antibody (ACPA) were associated with an increased likelihood of remission and low disease activity [17]. These findings suggest that the baseline HAQ could be a useful parameter for predicting remission. Actually, in the present study, the HAQ and ROM were identified as factors associated with the 52-week remission. However, the HAQ is in itself a parameter to check functional disabilities rather than a biomarker. From the viewpoint of biomarkers for monitoring treatment progress, ROM seems to be superior to HAQ.
In this study, the distribution of patients with CDAI-remission was the same as that of patients with SDAI- and Boolean-remission except for one patient. This leads to quite similar results, which are shown in Tables 2 and 3 and Figs. 1–3, between the remission and non-remission groups for CDAI and SDAI or Boolean standards. Because we used tocilizumab for approximately 40% (22/51) of patients, the SDAI and Boolean standards, which are affected by CRP, might have been evaluated better. If we used TNF-inhibitors for more patients, the distribution of patients for CDAI-remission and SDAI- or Boolean-remission may be altered.
A predictive factor for DAS28 remission was DAS28 at 12 weeks; however, this is an expected result. The serum ROM levels were not identified (p = 0.056). When DAS28 was excluded from independent variables, ROM and HAQ were again identified (OR: 0.985, 95%CI: 0.975–0.995, p = 0.005 for ROM; OR: 0.075, 95%CI: 0.010–0.570, p = 0.012 for HAQ, data not shown). DAS28 may differ among physicians and also is not a biomarker. Therefore, we believe that monitoring ROM values allows physicians to predict future remission rather than monitoring DAS28.
The strong points of this study are that we demonstrated the superiority of ROM to other clinical parameters used in routine clinical practice, such as CRP, MMP-3, DAS28, CDAI, and SDAI, as a predictor for the 52-week remission by CDAI, SDAI and Boolean standards. Although the ROM cut-off value that discriminates remission from non-remission does not have high sensitivity, controlling serum ROM levels tightly may allow patients to achieve remission by CDAI, SDAI and Boolean standards in the early stage during treatment with BAs.
This study has some limitations. First, the sample size was small, and background characteristics such as disease duration, PSL and MTX doses, and concomitant diseases varied among patients. Second, a variety of BAs, including TNF inhibitors and tocilizumab, were used. The effect of BAs on the inhibition of ROM may be different among BAs. Third, association of ROM with joint destruction has not been investigated. The relationship between serum ROM levels and radiographic progression of joint damage should be analyzed in the future. Fourth, although oxidative stress is involved in the pathophysiology of many diseases in humans [18–23], its role in the pathobiology of RA remains unclear. Further studies are required to establish the clinical significance of oxidative stress in RA.
In conclusion, the ROM serum level at 12 weeks after treatment initiation with BAs is a predictive factor of 52-week remission by CDAI, SDAI and Boolean standards. The ROM serum level may be a useful biomarker for achieving early remission in the current treatment strategy aiming at the early remission of RA.