This is the first study to assess the definition of dt-RA with respect to effectiveness and tolerance to the next b/tsDMARD. Based on the results of this study, we propose the definition of dt-RA to be failure to ≥ 2 csDMARDs and/or ≥ 4 b/tsDMARDs, because these cut-offs predict inadequate response to the next b/tsDMARD.
Refractoriness to a b/tsDMARDs is caused by a variety of mechanisms. Incorrect targeting is supported by studies that compared non–TNF-targeted bDMARDs and TNFis as second bDMARDs for patients with insufficient response to a first TNFi [11, 12]. For patients who received treatment with incorrect targeting, the probability of effectiveness of the next b/tsDMARD does not differ from that of the first treatment. This may explain the present result that no significant difference was observed between patients who failed ≥ 1, ≥ 2, and ≥ 3 b/tsDMARDs and the efficacy of the next b/tsDMARDs treatment (Table 2).
In contrast, multi-b/tsDMARD refractoriness may occur via different mechanisms. One possible explanation is induction of anti-drug antibodies (ADAbs) 15, which is more commonly observed among patients treated with TNFis than with other agents . Indeed, patients who previously developed ADAbs against a TNFi are reported to be more likely to develop additional ADAbs with subsequent TNFi treatment [14, 15]. The presence of ADAbs is associated with drug safety and tolerability as well as refractoriness , but no associations between cut-off values and the frequency of adverse events were observed in the present study (Figure 3). Therefore, further analyses are required to study the characteristics of patients with ≥ 4 failures to b/tsDMARDs.
Another reason for inadequate response to b/tsDMARD could be “false refractoriness,” which is characterised by persistent symptoms despite lack of inflammation . One cause of false refractoriness is increased comorbidity burden, which has been reported to lower response rate and retention rate of bDMARDs . The present finding that treatment failure to ≥ 4 b/tsDMARDs was not significantly correlated with markers of inflammation, such as CRP and ESR titres, but was associated with HAQ suggests that resistance to multiple b/tsDMARDs might be caused by increased comorbidity burden. However, GH was also weakly correlated with refractoriness in a mixed logistic model, so the mechanisms underlying refractoriness remain to be elucidated. In contrast, treatment failure to ≥ 2 csDMARDs was significantly correlated with ESR titre, which cannot be explained by the “false refractoriness” concept. Therefore, the mechanism of refractoriness observed in csDMARD treatment failure might be different from that in b/tsDMARD failure.
A previous study showed that two or more failures to csDMARDs were correlated with comorbidity burden in RA patients. As some comorbidities, such as interstitial lung disease, also increase the risk of infection, the correlation between ≥ 3 failures to csDMARDs and a higher hazard of infection (Figure 3) may be due to the comorbidities in patients who have experienced multiple failures to csDMARDs.
In an international survey, many rheumatologists mentioned characteristics other than joint symptoms as factors contributing to dt-RA, including extra-articular manifestations, comorbidities, side effects, and treatment non-adherence. The current study did not show a significant difference in the hazards of such events. However, based on the appearance of the cumulative hazard estimate graphs (Figure 2, 3), this absence of a significant association might be due to the sample size being too small.
A global consensus about the definition of dt-RA regarding use of glucocorticoids is failure to taper glucocorticoids to < 5-10 mg prednisone or equivalent daily . The present study showed that treatment with glucocorticoids was not associated with responsiveness to b/tsDMARDs but rather with hazard of severe infection that leads to treatment cessation. This result underlines the importance of using minimum doses of glucocorticoids, while considering the benefit of their use [19-21].
Our study is limited primarily by its inherently retrospective nature. In particular, there are several limitations related to data collection. Firstly, this registry included several episodes of the same patients who received different agents, because if all duplicates are excluded, the number of responders would be too small. Secondly, 905 patients (25%) had missing data about past usage of csDMARDs. This is mainly because many patients with long disease duration did not remember the past use of csDMARDs. Therefore, patients with longer duration might have been more likely to be excluded, which may have caused selection bias. Thirdly, as aforementioned, comorbidity data, such as chronic kidney disease and interstitial pneumonia, were not included, which could confound the outcomes.
Another limitation is that the number of patients varied by agent type. Although the mixed-effect model was applied to adjust for this difference, such methodology may not fully adjust for all confounders related to choices of treatments. In addition, the number of patients included in certain categories, such as ≥ 4 failures to b/tsDMARDs, was very small. Therefore, based on the Cox regression model illustrated in Figures 2 and 3, we cannot determine whether the absence of significant statistical difference indicates no difference or whether the sample size was too small to show a difference.
Finally, almost all the patients included in this study are Japanese with Asian ethnicity and a relatively small body size, among whom the risks of adverse events may be different from people of different ethnic or demographic backgrounds. Nevertheless, these limitations may not substantially impact the cut-off values we have proposed.
In conclusion, this study assessed cut-off values to be used to define dt-RA with regard to responsiveness to the next b/tsDMARD. Our results suggest that cut-offs of ≥ 2 failures to csDMARDs and/or ≥ 4 b/tsDMARDs are useful to predict dt-RA status.