Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that primarily affects the synovial joints. It is characterised by joint pain and functional disability that lead to reduced quality of life and a high socioeconomic burden (1). As an autoimmune disease, complex interactions among B cells, T cells, macrophages, neutrophils, dendritic cells, fibroblasts, and osteoclasts play crucial roles in initiating and maintaining inflammation of the joints (2). Among these, B cells appear to contribute significantly to the development of RA by producing pathogenic autoantibodies, presenting self-antigens to T cells, and secreting inflammatory cytokines (3). Therefore, B cells have emerged as therapeutic targets in treatment approaches involving direct depletion through monoclonal antibodies (mAb), inhibition of pro-inflammatory soluble factors or co-stimulatory molecules, and interruption of B cell activation or engagement of inhibitory checkpoint receptors (4). Despite the development of B cell-targeted treatment, the first therapeutic anti-CD20 mAb remains a crucial modality, with a long history of successful clinical use. In RA, the only biological agent approved for specific B cell-targeted therapy is rituximab, a chimeric monoclonal antibody against the CD20 antigen of B cells (5).

Rituximab was first used as a treatment for RA in 2006 and was approved for use with methotrexate (MTX) in patients with inappropriate responses to more than one anti-tumour necrosis factor agent (6). Clinical studies of rituximab have established its efficacy and safety as a protocol administered every 6 months after baseline. As such, the authorised dose regimen is intravenous infusion of 1,000 mg on days 1 and 15 every 24 weeks (7). However, although administration at intervals of 6 months may be the most appropriate, clinical responses may vary depending on seropositivity, biomarkers, and genetic markers given that reconstitution of the peripheral B cells usually occurs 6–9 months after rituximab administration (8, 9). Thus, determining the optimal timing for retreatment is challenging with respect to the duration of the effect. Further, safety is also of primary concern as repeated administration of rituximab may cause immunoglobulin reduction and increase the risk of infection. A comparison of the clinical effects of administration at reduced doses showed similar clinical effects at a reduced dose (one infusion of 1,000 mg or two doses of 500 mg) after a first course of rituximab at standard doses (10, 11). In addition, a recent real-world study on the use of rituximab showed that on-demand administration maintains good clinical responses (12).

Retreatment options for rituximab include regular retreatment at fixed intervals (e.g., every 6 months), treatment of flare, or treatment with any deterioration or treatment-to-target (13). This study aimed to investigate the patterns of use of rituximab in patients with RA in the real world, using the KOrean Rheumatology BIOlogics registry (KOBIO). Furthermore, we analysed the persistence rates of rituximab treatment and identified the factors associated with extending the administration intervals and with treatment failure.

On-demand rituximab administration has been reported to achieve outcomes similar to fixed-interval administration. In this study, 57 patients among the 82 patients were treated with on-demand rituximab administration without failure, and 10 of them achieved biologic-free remission after the first cycle. The mean time interval of the retreatment courses was 16.3 ± 8.7 months. Rituximab has a longer-lasting effect on the host immune system than other biologic agents approved for the treatment of RA owing to its depletion of peripheral B cells from about 90% to almost 100% (18). However, although the long-lasting effect is highly advantageous for patients who prefer a convenient lifestyle, there are concerns that early use of new biologic agents may pose additional safety risks even if the effect of rituximab is insufficient.

Given that it is difficult to cope with insufficient efficacy, it is necessary to select subjects who are predicted to be good responders to rituximab. As such, the significance of this report is emphasised as, to our best knowledge, it is the first to evaluate the treatment response to rituximab using the nationwide registry in Korea. In our study, 72.4% of patients with RA continued rituximab after 5 years, indicating higher effectiveness and tolerability than previously reported in other cohorts. The rate of persistence in most previous reports ranged from 50-60% after 4 years of rituximab (19–21). The reason for this trend is unclear because there are no differences in disease activity, seropositivity, or number of prior biologic agents between our study and other studies (19, 20).

In the present study, the time interval for patients maintaining rituximab was significantly longer than the fixed retreatment schedule of 6 months. Retreatment was performed on demand rather than on a fixed schedule, as the retreatment schedule in Korea depends highly on the Korean National Health Insurance (KNHI) reimbursement criteria. Unlike other biologic agents that are administered at regular intervals even without flare, rituximab is reimbursed only at the time of flare at least 6 months after administration of the previous course under the KNHI system. A total of 12% of patients in this study achieved biologic-free remission after 1 cycle of rituximab. Given that existing data are mainly on patients who achieved biologic-free remission following treatment with anti-TNF agents, there is limited evidence on whether biologic-free remission is sustained after the discontinuation of rituximab (22).

In a previous study, the sustained rate of biologic-free remission ranged from 14 to 60% within a short follow-up period of 2 years, and thus further studies to select the most appropriate treatment strategies are needed (23). Compared with previous studies, our study is advantageous in that it includes a fairly long follow-up period, and we found a novel result that the use of two or more anti-TNF agents prior to rituximab is the only significant factor influencing biologic-free remission. This is in contrast to previous results that a higher number of biological agents prior to rituximab experience leads to a shorter duration of the clinical response (24, 25). A study by La et al. (26) verified that prolonged exposure to anti-TNF agents could increase B-cell survival factors to induce resistance to rituximab, and this is related to the overall duration of previous anti-TNF agents, rather than the number of anti-TNF failures. In summary, instead of long-term maintenance, the anti-TNF agent should be switched in patients who do not adequately respond to the treatment.

Further, other biologic agents with a different mechanism of action, such as rituximab, should be selected if the patient does not respond to treatment with two or more anti-TNF agents. Furthermore, RF negativity, not smoking and minimal radiographic damage which have been proven to be related to biologic free remission in previous studies, have not shown significant results in this study (27). The lack of significance of baseline disease characteristics for predicting biologic-free remission after treatment implies that other factors such as genetic differences in drug metabolism may affect the response to rituximab (28, 29).

Increasing evidence shows that on-demand, rather than fixed regular retreatment, is a reasonable schedule for long-term maintenance treatment of rituximab in patients with RA (30). The time interval for the average rituximab treatment course in our patients was 16 months, which was longer than in published literature (12, 20, 31). In several real-life observational studies, the average response duration of rituximab ranged from 7.8 months to 13 months. Observational studies also demonstrated that fixed regular retreatment and on-demand retreatment with rituximab showed comparable efficacy in patients who had a good response after the first cycle of the standard regimen (30). As such, on-demand retreatment is a more favourable option with respect to safety and cost saving than fixed regular retreatment. Several studies on low-dose rituximab as retreatment to reduce side effects have proven the non-inferiority of its efficacy; however, the on-demand retreatment of low-dose rituximab has insufficient efficacy (32, 33).

Considering the current tendency to pursue on-demand retreatment globally and the convenience of extending the retreatment time intervals, it is reasonable to find ways to extend the time interval between retreatment courses rather than attempting to reduce the dose. Our study identified that prior or concomitant use of two or more csDMARDs and concomitant use of corticosteroids are associated with the extension of the time interval. Previous studies have reported that concomitant treatment with csDMARDs improves the clinical response of rituximab, and most of these studies are on rituximab in combination with a single csDMARD (34–36). To our best knowledge, we are the first to report that the concomitant use of two or more csDMARDs and/or corticosteroids with rituximab plays a critical role in maintaining clinical good responses for long periods. It is quite noteworthy in that it has an acceptable safety profile when compared to concomitant use of csDMARD monotherapy (data not shown). This finding indicates that maintaining low disease activity to prevent disease flare following rituximab treatment is important for extending the time interval between treatment courses. The persistent rates of rituximab were high in our cohort owing to the high proportion of patients taking concomitant csDMARDs or corticosteroids.

The treatment failure rate in this study was 18.3%, which is lower than that in other studies (19, 20). However, the most common reasons for treatment failure (i.e., lack of efficacy, death, and adverse events) were similar to those in previous studies (19). Binary logistic regression analysis showed that only anti-CCP Ab positivity is a significant associated factor of treatment failure. RA patients who are RF or anti-CCP Ab positive are more likely to respond better to rituximab treatment than autoantibody-negative patients. However, studies on each antibody as independent factors have reported conflicting results (24, 37–39). Some studies reported that anti-CCP Ab positivity was associated with a good response and that higher anti-CCP Ab titres predict good responses (40, 41). Meanwhile, other study reported that it is RF positivity, rather than anti-CCP Ab positivity, that is related to the good response to rituximab (25). Thus, the most reliable antibody to predict treatment response is yet to be established.

In addition, other factors, such as the B cell phenotype, have been recently reported to influence the treatment response to rituximab (42, 43). Plasmablasts, for example, was supplemented CD20 positive B cells despite being CD20 negative, becoming a potential biomarker for identifying B cell depletion after treatment with rituximab (44). However, except for anti-CCP Ab, no useful biomarkers predictive of treatment failure have been identified. Although factors other than autoantibody positivity may affect treatment failure in rituximab, rituximab should not be considered as the primary treatment option in autoantibody-negative patients.

The strength of our study is that to our best knowledge, it is the first to analyse the factors that extend the time interval during on-demand retreatment with rituximab in RA patients with a good clinical response. In addition, this is the first study to investigate the treatment outcomes of rituximab in RA patients, using data from a nationwide registry. However, our study also has some limitations. First, the observational study design can lead to an underestimation of events by relying on passive reporting such as adverse events and deaths. Further, the rate of loss to follow-up is also higher than in clinical trials. Second is the possibility of selection bias from the assignment of biological agents because the decision to use rituximab was made by the treating rheumatologist. Finally, the data from the KOBIO registry are not representative of the entire population of RA patients treated with rituximab. Given that data were mainly from outpatients, only a small portion of the patients may have been included in the registry because national guidelines require admission for the intravenous administration of biological agents. This limitation may be overcome with recruitment of additional patients from multicentre.

RA patients treated with rituximab in Korea show high persistence rates. Further, the time interval between the retreatment courses was longer than in other countries. Concomitant use of two or more csDMARDs and concomitant use of corticosteroids with rituximab are significant influencing factors of extending the retreatment time interval. Importantly, an extended interval is safe and cost-efficient. These findings should be considered when selecting rituximab as a treatment for patients with RA.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Institutional Review Board of Ajou University Hospital (AJIRB-MED-MDB-21-055). The participants provided their written informed consent to participate in this study.

J-WK, J-YJ, KS, C-HS, and H-AK contributed to the study design and data collection, analysis, and interpretation. J-WK, KS, and H-AK contributed to the data collection and/or data interpretation. All authors revised the manuscript and gave final approval for submission.

This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI16C0992).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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