RA is a prevalent rheumatic disease primarily affecting the joints. If left uncontrolled, it can result in joint destruction and deformity, significantly compromising patients' quality of life. In severe cases, vital organs such as the heart and lungs may also be involved, posing life-threatening risks. Consequently, patient treatment requirements and expectations are often elevated. According to EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update,with poor prognostic factors, any bDMARD should be added to the csDMARD; tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD is recommended[9]. The response to csDMARD combined with single bDMARD or tsDMARD remains unsatisfactory in a subset of patients.
The efficacy of switching to JAKi has been extensively reported for RA patients who have inadequate responses to csDMARDs or bDMARDs. Overall response rates, such as the ACR20 response rate, ranged from 52% to 73%[10-14]. At our center, many patients were switched to JAKi due to an inadequate response to bDMARDs. Some patients exhibited improved disease outcomes following JAKi treatment, while others experienced poor disease outcomes with exclusive JAK inhibitor therapy. Therefore, in this study, an attempt was made to combine bDMARDs with JAKi tofacitinib. The findings demonstrated that the majority of patients exhibited a favorable and prompt response, with notable reductions in ESR and CRP observed in certain individuals following 4 weeks of treatment, refer to Figures 3 and 4. In addition, mid- and long-term evaluation up to 60 weeks (> 1 year) showed that patients with combination therapy had better inflammatory control and disease remission than those with switch therapy. The findings suggest that combination therapy may yield superior treatment outcomes in the short to medium term, compared with monotherapy using either agent.
The existing literature on the combination of bdMARDs and tsDMARDs is limited, probably because of academics raising significant concerns regarding potential adverse events including serious infections, cardiovascular complications, thrombotic events, and malignancies[15]. Our research team has conducted a trial evaluating the efficacy and safety of combining tofacitinib with bDMRAD in the treatment of ankylosing spondylitis (AS), and preliminary findings from small-scale studies have demonstrated favorable results[16]. Considering the advanced age and increased vulnerability of RA patients compared to those with AS, comprehensive screening for tuberculosis and hepatitis B virus (HBV) is conducted before commencing treatment with bDMARDs or tsDMARDs in all RA patients. Furthermore, in cases where inadequate response is observed among a subgroup of RA patients receiving bDMARDs, cautious consideration is given towards incorporating tofacitinib therapy alongside intensified monitoring protocols. These factors account for the restricted sample size encountered within this study. In the present study, we observed four cases of herpes zoster and eight cases of mild URTI in the group receiving bDMARDs combined with JAKi tofacitinib, all of whom had herpes zoster were aged over 60 years. The occurrence of herpes zoster as an adverse reaction to JAKi is frequently observed. According to the available literature, the reported incidence of herpes zoster associated with tofacitinib ranges from 5-10%. In this study, there were four cases (14.3%) of herpes zoster documented[17-19]. The higher proportion may be attributed to the combination of bDMARDs; however, all patients achieved recovery following antiviral treatment, and no patient discontinued their course of treatment. The risk of infection, such as herpes zoster, is considered manageable; however, heightened caution should be exercised in elderly patients aged over 60 years.
Our study is subject to several limitations. Firstly, the results and outcomes may be influenced by confounding factors such as the patient's lifestyle habits, comorbidities, and other medications taken for reasons unrelated to bDMARDs. Nonpharmacological interventions, such as smoking cessation, maintaining thermal comfort, and engaging in appropriate exercise, were recommended for each patient. However, the quantification of their effectiveness is hindered by objective local conditions, subjective patient compliance, and the retrospective nature of the study design. These potential confounding factors cannot be definitively ruled out. The limited sample size and short treatment duration prevented us from obtaining long-term outcomes or observing potential adverse events associated with prolonged use. The unavailability of the selective T cell costimulation blocker abatacept and B cell inhibitor rituximab in our unit due to objective conditions precludes the inclusion of bDMARDs targeting these mechanisms of action in this study[20,21]. The retrospective nature of this study may have introduced selection bias due to the lack of strict inclusion and exclusion criteria, resulting in a diminished level of evidence-based support. Furthermore, as all data were solely obtained from the Fourth Affiliated Hospital of Zhejiang University School of Medicine, which represents a single-center setting, the generalizability of these findings to other hospitals may be limited.
In conclusion, our findings offer some evidence, to a certain extent, supporting the effectiveness and safety of combining bDMARD with JAKi tofacitinib in RA patients who have an inadequate response to bDMARD monotherapy. This combination effectively manages disease activity while maintaining a relatively low and manageable incidence of adverse events.The aim of our study is to contribute valuable insights in this area. In order to establish evidence-based medical support, it is imperative to conduct prospective randomized controlled studies with large sample sizes and meticulously designed research protocols in the future.