A total of 2292 patients were encompassed within the scope of this analysis. The utilization of molecular targeted therapies exhibited significant variability across different age groups, wherein TNF inhibitors emerged as the prevailing choice (43.5%) for patients below the age of 65, while JAK inhibitors were administered to 17.1% of the patient population (Fig. 1). Conversely, there was a notable escalation in the utilization of CTLA4-Ig among individuals within the age range of 65–74 years. Furthermore, in the subset of patients aged 75 years and above, the percentage of JAK inhibitors employed experienced a decline (7.8%), while abatacept emerged as the prevailing choice (39.2%). On the other hand, anti-IL-6R antibodies were administered to approximately 25% of individuals across all age groups, and the utilization rate remained consistent irrespective of age.

Patient disposition. bDMARDs biologic disease-modifying anti-rheumatic drug, tsDMARDs targeted synthetic disease-modifying anti-rheumatic drugs, TNFi tumor necrosis factor inhibitors, Anti IL-6R anti-IL-6 receptor antibodies, CTLA-4 Ig cytotoxic T lymphocyte antigen 4 immunoglobulin, JAKi Janus kinase inhibitors

Table 1 shows the patient profiles corresponding to each age group. Within these generational patient backgrounds, notable variations were observed not only in terms of age but also across several clinical factors. For instance, it is well established that the male-to-female ratio tends to shift towards a higher proportion of male patients among elderly patients with RA. In the present study, it was observed that among patients below 65 years of age, women accounted for 84.5% of the population, whereas among those aged 75 years and above, women constituted 77.6% (p < 0.001) [20]. As a fundamental principle, the participating centers in this study adhered to the EULAR treatment recommendations for RA and employed methotrexate (MTX) as a therapeutic approach in phase I, unless contraindications were present. However, only 53.2% of patients aged 75 years or older received MTX treatment.

The long-term retention rate serves as an indicator, reflecting the balance between the safety and efficacy of the drug over an extended period. Taking into account the significant discrepancies in patient backgrounds observed across different drugs (Supplementary Tables 1, 2, and 3), all subsequent analyses were carried out following the adjustment of potential patient selection bias using the PS-based IPTW approach (Tables 2, 3, and 4). Initially, we investigated the 3-year persistence rate specifically for patients aged 50 years or older. The analysis revealed that the persistence rate for TNF inhibitors was lower compared to other preparations. However, there were no significant differences in the persistence rate among anti-IL-6R antibodies, CTLA4-Ig, and JAK inhibitors, as demonstrated in Fig. 2a. However, when comparing the 3-year retention rates of each molecular targeted therapy across different age groups, notable variations were observed (Fig. 2b). In the younger age group (< 65 years), JAK inhibitors and anti-IL-6R antibodies exhibited higher persistence rates compared to the other two therapies (p < 0.001). Conversely, among individuals aged 65–74 years, higher retention rates were observed for JAK inhibitors and CTLA4-Ig (p < 0.001). Furthermore, among those aged 75 years and older, CTLA4-Ig and anti-IL-6R antibodies agents demonstrated higher continuation rates (p < 0.001).

Drug retention rates and factors influencing discontinuation. a Retention rates in patients aged 50 and above. b Retention rates across different generations. c Reasons for drug discontinuation across different generations. TNFi tumor necrosis factor inhibitors, Anti IL-6R anti-IL-6 receptor antibodies, CTLA-4 Ig cytotoxic T lymphocyte antigen 4 immunoglobulin, JAKi Janus kinase inhibitors, AEs adverse events

To explore the factors contributing to discontinuation in each age group, an analysis was conducted of the reasons for discontinuation categorized by age. The findings indicated that ineffectiveness was the most prevalent reason for discontinuation across all age groups (Fig. 2c). However, the proportion of patients discontinuing or switching because of ineffectiveness varied among age groups. Specifically, in the younger age group (< 65 years), approximately 68.8% of patients experienced discontinuation or switch due to ineffectiveness, whereas this proportion decreased to around 50% for patients aged 65, and it remained at a similar level for those aged 75 and older. On the contrary, discontinuations attributed to infection were infrequent among patients younger than 65 years, accounting for only 1.8% of cases. However, the proportion increased to 9.1% in patients aged 65 years and older and further rose to 13.2% among patients aged 75 years and older. The findings of the ORAL Surveillance study have sparked concerns regarding the incidence of malignancies associated with JAK inhibitors. In the study, 2.9% of younger patients discontinued b/tsDMARDs because of malignancy. The proportion increased to 5.8% among patients aged 65 to 74 years and 5.5% among patients aged older than 75 years.

As depicted in Fig. 2, the primary reasons for discontinuation of b/tsDMARDs were categorized as “insufficient efficacy,” “infection,” “allergic reaction,” and “cancers.” Consequently, our subsequent analysis focused on evaluating the incidence of these factors in each drug specifically among patients aged 50 years or older. This approach aligns with the age criteria employed in the ORAL Surveillance study. However, it is important to acknowledge that our results may not be directly comparable to those of the ORAL Surveillance study because of differences in study design and patient characteristics. Furthermore, we examined these incidences within different age groups to gain a comprehensive understanding of the associations. Among patients aged 50 years and older, the rates of discontinuation due to insufficient efficacy were the lowest for anti-IL-6R antibodies and JAK inhibitors. Similarly, the rates of discontinuation due to allergic reactions were the lowest for CTLA4-Ig and JAK inhibitors. However, the rates of infections and cancers were similar across all drugs (Fig. 3a–c).

Incident rates of drug discontinuation reasons. Incidence rates of a insufficient efficacy, b serious infection, c allergic reaction, or d cancers as a cause for drug discontinuation across different generations. Yr year, NMSC non-melanoma skin cancer, TNFi tumor necrosis factor inhibitors, Anti IL-6R anti-IL-6 receptor antibodies, CTLA-4 Ig cytotoxic T lymphocyte antigen 4 immunoglobulin, JAKi Janus kinase inhibitors

However, distinct trends emerged when analyzed by age groups. The discontinuation rates due to insufficient efficacy consistently remained the lowest for JAK inhibitors across all age groups (Fig. 3a). Regarding discontinuations due to infection, they were comparable for all drugs in patients below 65 years of age, with minimal instances (Fig. 3b). However, a notable trend towards increased discontinuations due to infection was observed for JAK inhibitors and anti-IL-6R antibodies in patients aged 65 years and older (p = 0.13). Moreover, there was a significant rise in infections, particularly among patients aged 75 years and older who received JAK inhibitors (p = 0.01). On the contrary, CTLA4-Ig exhibited a lower rate of discontinuations due to infection across all age groups. Discontinuations attributed to allergic reactions, including injection site reactions, were primarily associated with TNF inhibitors, followed by anti-IL-6R antibodies. In contrast, allergic reactions were rarely observed with CTLA4-Ig and JAK inhibitors (Fig. 3c). This indicates that allergic reactions might contribute to the comparatively lower retention rate of TNF inhibitors in comparison to other drugs. Notably, this trend was more pronounced in older patients. No significant differences were found in the incidence of malignancies among all the various drugs.

The findings from the ORAL Surveillance study have brought forth apprehensions about the occurrence of cancers and MACE linked to the utilization of JAK inhibitors. This study possesses a distinct patient background and study design when compared to the ORAL Surveillance study, making direct comparisons challenging. However, it remains a significant concern to assess the risks of malignancy and MACE in patients encountered in routine clinical practice. Subsequently, we proceeded to examine the incidence of cancers and MACE associated with the use of each molecular targeted therapy, with TNF inhibitors employed as the reference for comparative analysis. Figure 4a shows the hazard rates for the incidence of cancers in all patients, revealing no significant differences in the incidence of cancers among all drugs compared to TNF inhibitors. Furthermore, when examining participants aged 50 years or older, the trend remained consistent, with no noticeable increase in the incidence of cancers with JAK inhibitors or other molecular targeted therapies in this registry (Fig. 4b). This trend persisted even among participants aged 65 years and older, who were considered to be at a higher risk, as demonstrated in Fig. 4c.

Hazard ratios for cancers, excluding NMSC. Hazard ratios for cancers, excluding NMSC in a all patients, b patients aged 50 and above, c patients aged 65 and above. NMSC non-melanoma skin cancer, CI confidence interval, TNF tumor necrosis factor, JAK Janus kinase, Anti IL-6R anti-IL-6 receptor antibodies, CTLA-4 Ig cytotoxic T lymphocyte antigen 4 immunoglobulin

In contrast, when the incidence of MACE was examined, the overall incidence in this study was very low. Specifically, it was 0.9% for TNF inhibitors, 0.2% for CTLA4-Ig, 0.5% for anti-IL-6R antibodies, and zero for JAK inhibitors over 3 years. The hazard rates also revealed no significant differences among all drugs, as indicated in Supplementary Fig. 1A. These findings remained consistent when analyzing the data for patients aged 50 years and older (Supplementary Fig. 1B) as well as those aged 65 years and older (Supplementary Fig. 1C).