Biological agents targeting inflammatory cytokines are more effective at suppressing progression of joint damage than are conventional DMARDs. However, previously reported studies on the efficacies of these agents for slowing radiological damage showed that there was still significant progression in many patients [1
]. These data allowed us to recognize that many patients on nonbiologic DMARDs show no radiographic progression, and some even show radiographic improvement. Specifically, our previous data showed that 39% of patients treated with conventional DMARDs showed no radiographic progression in 1-year follow-up [10
]. However, biological agents may have side effects. With such knowledge gained from growing experience in the use of biologics, patients would benefit from personalized therapies based on accurate prognostic tools rather than standard therapies that do not evaluate risk factor to guide treatment selection. A better understanding of the prognostic factors for progressive joint damage under nonbiological treatment and appropriate targeting of biologics to patients with RA at high risk of progressive joint damage and disability could enhance risk–benefit balance of RA therapeutic strategies. Thus, many investigators have sought such prognostic factors. Young-Min et al. reported the possible usefulness of matrix metalloproteinase-3 (MMP-3) and uCTX-II in predicting radiographic outcome in RA patients treated with DMARDs [14
], and Charni et al. reported the possible usefulness of urinary type II collagen helical peptide (HELIX-II) [15
]. We found that high baseline levels of uCTX-II, uPYD/DPD, JSN score, and low BMI were independently significantly associated with 1-year progression of joint destruction under conventional DMARDs treatment [12
]. Most of these newly developed or recognized markers are still not widely used in clinical practice; however, further understanding the significance of these markers would facilitate better therapies. Having established these risk factors, the efficacy of biologics for reducing joint destruction in high-risk groups needed to be confirmed to effectively target treatment. Therefore, in this study, subanalysis from a prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) was performed to investigate the ability of this agent to reduce progression of structural joint damage in high-risk patients. There was no significant difference in 1-year changes of JSN scores between DMARD- and tocilizumab-treated patients in high-risk groups, as estimated by high uCTX-II, uPYD/DPD. Our data show, however, that tocilizumab monotherapy effectively blocked progression of bone erosion in all high-risk groups as estimated by high uCTX-II, uPYD/DPD, or low BMI and also effectively blocked progression of JSN in high-risk groups as estimated by low BMI or high JSN score, The differences in 1-year changes of erosion and JSN scores between the DMARD- and tocilizumab-treated patients were greatest in the high-risk groups, whereas there was little to no difference in the low-risk group. These findings indicate that the benefit of tocilizumab monotherapy to inhibit bone erosion and JSN progression is maximized in high-risk groups as estimated by high uCTX-II, uPYD/DPD, or low BMI, and by low BMI or high JSN score, respectively. To our knowledge, this is the first comprehensive report showing the usefulness of biomarker targeting strategies for biologics in treating RA. There were smaller and nonsignificant differences in 1-year changes of erosion and JSN scores between patients in the DMARD or tocilizumab monotherapy treatment groups in the low-risk category, although progression was still lower in individuals receiving tocilizumab. The lack of statistical significance can be due in part to the very limited progression in the low-risk group reducing the power to detect differences. These findings also suggest that patients at low risk may benefit less from treatment with biologics unless they develop changes in markers that indicate an increased risk of progression during treatment with conventional DMARDs. On the other hand, the lack of statistically significant differences in 1-year changes of JSN scores between patients in the DMARD or tocilizumab monotherapy treatment groups in the high-risk category might be due to the relatively weak prognostic power of high uCTX-II and uPYD/DPD for JSN progression compared with low BMI or high JSN score [12
Establishing means of early discrimination between tocilizumab radiological responders and nonresponders is therefore raised as the next issue to be addressed when considering targeted therapeutic strategies. In conclusion, we demonstrated that tocilizumab monotherapy is effective in reducing radiological progression in patients presenting with risk factors for rapid progression of joint damage.