We characterized the long-term prognosis of RA patients with persistent moderate disease activity (MDA) under bDMARD treatment in the context of clinical practice. We found that a substantial proportion of patients improved disease activity status and function after treatment, yet a substantial proportion exhibited pMDA irrespective of treatment modifications. Most importantly, pMDA was associated with worse long-term (5-year) outcomes (functional limitation and serious adverse events) than persistent lower inflammatory burden. Interestingly, the subgroup with plMDA had better long-term outcomes than those with phMDA.
An important finding of this study was that persistent MDA was linked to significantly worse functionality trajectory during 5 years of bDMARDs therapy, as compared to pRLDA (Fig. 3 and Table 2). Interestingly, residual disease activity was the major contributor to HAQ increase over time (Table 2). These data are comparable to those from early RA cohorts on csDMARDs assessing the cumulative effect of disease activity on RA-related outcomes [9, 10, 12]. Although one might argue that this finding is an expected one, we considered it clinically important and novel to focus for the first time on patients treated with bDMARDs, which might exert differential immunomodulatory effects as compared to csDMARDs. For example, it has been shown that both TNFi and tocilizumab may inhibit joint destruction effectively even when residual disease activity exists, which is not the case for methotrexate [13,14,15].
Another key finding of our study is that MDA patients comprise a heterogeneous group in terms of outcome. Patients with plMDA have significantly better 5-year functionality trajectory than those in phMDA (Fig. 3 and Table 3). This agrees with studies focusing on early-onset RA and csDMARDs treatments, showing that patients on the lower end of MDA have significantly better outcomes than those on the higher end [10, 16]. Notwithstanding the fact that observational studies cannot provide direct support for management strategies, we consider our results to be of clinical importance and relevant to the T2T concept. Firstly, our data provide further support to the validity of T2T in clinical practice, since there was a clear superiority for all long-term outcomes in the pRLDA as compared to pMDA group. Moreover, the heterogeneity of outcomes in lower and higher MDA patients can assist T2T strategies to tailor treatments for these subgroups in order to improve outcomes.
An interesting finding was that patients on pMDA accumulated more SAEs compared to patients on pRLDA during 5 years of bDMARDs therapy (Fig. 4). Additionally, the analysis within pMDA showed that subgroup phMDA had more SAEs than plMDA at 5 years of therapy (Fig. 4). A major contributor in SAE is serious infections. The correlation between disease activity level and serious infections has been shown by several cohort studies [17,18,19]. Nevertheless, only our study and the analysis from the CORRONA registry by Accortt et al. are those analyzing “cumulative” disease activity levels, revealing the significant “dose effect” of inflammatory burden on the risk for serious infections [20]. Moreover, data from the Nijmegen early RA inception cohort have shown that time-averaged disease activity burden contributes to the risk of cardiovascular events in RA patients on different background therapies [21, 22]. These findings combined with the finding of higher functional decline of pMDA group underline the importance of cumulative residual disease activity as an important contributor in RA long-term prognosis.
Long-term prognosis of RA largely depends on the disease inflammatory burden and associated comorbidities. One of the limitations in the literature is that the majority of short- and even long-term studies evaluate RA-related inflammation cross-sectionally. However, values representative of longitudinal course of disease activity and its effect over time are considered to provide more valuable information. One such approach is the average disease activity from multiple years of treatment [10], while another is the area under the curve of DAS28 course (AUC) which was associated with both radiographic progression [23] and the risk for cardiovascular diseases (CVD) [21, 22]. In the present study, we applied another approach using the cumulative time percentage (CTP) that DAS28 falls within a specified range during follow-up (CTP of DAS28-range), as indicative of long-term longitudinal disease activity course. We considered the AUC method not appropriate since it may not be able to distinguish a persistent moderate disease trajectory from one fluctuating equally between low and high disease activity levels which may exhibit approximately equivalent AUC values.
Studies analyzing persistent disease activity status from cohorts of biologics have focused on persistent remission [24,25,26,27,28,29,30]. Herein, we focused on persistent residual disease activity (pMDA), and we found that from patients in persistent moderate or lower inflammatory burden treated on bDMARDs, 23% were classified in a persistent low or remission status while 77% still exhibited substantial inflammatory burden (pMDA) after 5 years of therapy. Even though this seems as a rather high number, yet available data from registries have shown that only 8.2–21% of bDMARDs treated patients are classified as being in persistent remission [24,25,26,27, 29]. Of note, pMDA patients in our cohort differ from pRLDA even from baseline and could be divided further in two heterogeneous subgroups.
Early predictors for patient classification in pRLDA compared to pMDA group identified in multivariable predictive modeling were male gender, lower baseline, and lower first semester disease activity (DAS28) and functionality improvement in first semester compared to baseline (ΔHAQ < − 0.22) (Table 4). Comparable to our data, a meta-analysis of six studies for factors associated to sustained remission in patients treated with TNF inhibitors showed that greater baseline disease activity, age, disease duration, baseline functional impairment, and female sex were associated with reduced likelihood of achieving sustained remission [30]. Nevertheless, prediction of response at individual level is not yet clinically available. Future studies should enrich the predictive models with additional biological parameters aiming to further increase the predictive performance of current tools.
One of the limitations of this study is patients’ missing follow-up data. In order to address missing data and also maintain data quality, we excluded patients with large percentage of missing DAS28-data (> 50%) and imputed missing DAS28-data in the rest of the patients. Of note, the imputed-dataset (385 patients) compared to the non-imputed (292 patients) included additionally 93 (24%) patients, and results were similar in both datasets (groups pRLDA and pMDA differentiated in functionality trajectory and SAEs, data not shown).
Another limitation of this study can be considered the merging of remission and low disease activity groups. The pRLDA group included 52 patients in persistent remission, 20 in persistent low disease activity, and 18 with fluctuations between low and remission disease activity. Future studies in larger datasets could focus in persistent strictly low (2.6 ≤ DAS28 ≤ 3.2) and persistent moderate (3.2 < DAS28 ≤ 5.1) disease activity comparison.
In order to evaluate the robustness of the methodological approach, we performed sensitivity analysis in shorter (3-year) therapy duration with similar results (groups pRLDA and pMDA differentiated in functionality trajectory). Furthermore, analysis on groups’ differences regarding patients’ inclusion-year (year ≤ 2007, 2007 < year ≤ 2010, year > 2010) did not yield significant variation between the groups.
Conclusions
Our analysis revealed that a considerable proportion of RA patients on bDMARDs in clinical practice, although improve disease activity status, still manifests persistent moderate disease activity. This state was associated with adverse 5-year outcomes and was also found to present internal heterogeneity, while predictors were analyzed to assist for early patient classification. These findings further support the value of T2T strategy in order to improve long-term outcome and highlight the need for further targeted studies on persistent MDA state and its heterogeneous subgroups.