Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionized the treatment of chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), over the past two decades.1 These drugs have significantly improved the clinical and functional outcomes of RA, changed the disease course and enhanced the quality of life of patients.

The bDMARDs are indicated for those who responded inadequately to conventional synthetic DMARDs (csDMARD) or experienced side effects with these drugs. They are highly effective, enabling a high percentage of patients to achieve sustained remission or low disease activity.1–4 However, a significant number of patients treated with bDMARD failed to respond adequately or had an insufficient response, some of them within the few first months of treatment. The underlying reasons for these outcomes and the specific characteristics of such patients have yet to be fully investigated and understood.

While many studies have investigated the predictors of effectiveness and persistence in anti-TNF-α therapy, there has been a notable scarcity of studies that have evaluated the causes of early failure of these drugs.5–7 Some studies have primarily focused on the causes of discontinuation of bDMARDs in long-term treatment, however the factors linked to the early failure of bDMARDs in the first year of therapy have been poorly investigated.8–10

Given the limited knowledge in this area and the importance of identifying potentially modifiable risk factors for early bDMARD failure in patients with RA, this study was conducted. The study aimed to determine the percentage of RA patients who need to switch due to ineffectiveness in the first year of treatment and to investigate the risk factors associated with switching during the first year of bDMARD therapy in a cohort of Portuguese patients with RA.

A total of 437 (364 females, 83.3%) patients with RA were included. The mean age was 52.4±11.4 years and the disease duration was 11.8±8.8 years. The majority of these patients started an anti-TNF-α agent as first bDMARD (n=315, 72.1%). The remaining patients started rituximab (n=66, 15.1%), tocilizumab (n=51, 11.7%) and abatacept (n=5, 1.1%).

Forty-eight (11.0%) patients failed to respond to the bDMARD in the first year of treatment and needed to switch to another bDMARD. The mean duration of first bDMARD treatment in patients that needed to switch was 0.75±0.3 years. The switching rate was higher among the anti-TNF-α agents, as described in Table 1.

Demographic characteristics were similar in the group of patients that switch due to ineffectiveness and patients that did not switch in the first year. Gender, disease duration, age at onset, disease activity scores (DAS-28-CPR, CDAI, SDAI), functional scores (HAQ) and inflammatory parameters at baseline were also similar in the two groups. There were significantly more current or former smokers in the group of patients that needed to switch in the first year of therapy (p=0.030). Moreover, depression was significantly more frequent in the switch group (p=0.003). Positivity for RF at baseline was also significantly more frequent in the switch group (p=0.014).

Regarding the type of bDMARD, patients in the switch group were more frequently treated with anti-TNF-α agents (p<0.001). Table 2 describes demographic and disease characteristics, laboratory parameters, disease activity at baseline and treatment at baseline of the included patients.

In the multivariate analysis adjusted for gender and age, anti-TNF-α agents use (versus non-anti-TNF-α agents) (OR 8.3, 95% CI 2.4–28.8, p=0.001), tobacco exposure (OR 2.3, 95% CI 1.1–4.8, p=0.02) and history of depression (OR 3.1, 95% CI 1.3–7.7) seem to predict the need to switch due to ineffectiveness in the first year of treatment, as shown in Table 3.

In this study, the switching rate due to ineffectiveness was 11.0% for all bDMARDs. Specifically, it was 14.3% (with a range between 3.3% and 38.5% depending on the subtype of anti-TNF-α agent) for anti-TNF-α agents, 2% for tocilizumab and 3% for rituximab. A previous systematic review found a bDMARD discontinuation rate due to ineffectiveness in the first year of 14%, ranging from 10% to 19%.17 Furthermore, a study that analyzed the discontinuation rate of etanercept during the first year of treatment also reported a similar rate of 14.7%.10 In this study, anti-TNF-α agents exhibited a higher discontinuation rate compared to non-anti-TNF-α agents, specifically tocilizumab, rituximab, and abatacept. This finding is consistent with previous literature. Previous studies indicated that abatacept and tocilizumab had lower discontinuation rate due to inefficacy than anti-TNF-α within the first 36 months, with this difference being already observed at 12 months of therapy.18 Additionally, research suggests that patients on abatacept switched less frequently than those on anti-TNF-α in the first 12 months of treatment.19,20 Rituximab also appeared to have lower discontinuation rate due to inefficacy compared to anti-TNF-α, which is consistent with the findings of this study.20,21

In this study, current and former smokers, patients with depression and those with positive RF and history of rheumatoid vasculitis had a higher rate of switching due to ineffectiveness. This analysis identified tobacco exposure, history of depression and the use of anti-TNF-α agents as predictive factors for switching due to ineffectiveness in the first year of treatment.

Seropositivity for RF and ACPA has been linked to a more aggressive and active form of RA.22,23 This increased disease aggressiveness may explain why RF-positive patients more frequently required to switch the treatment within the first year. However, we observed an association only with RF and not with ACPA. Interestingly, Santos-Moreno et al. reported similar findings in their study. They noted that remission was less frequent among RF-positive patients treated with anti-TNF-α agents compared to RF-negative patients, with no differences being reported in the remission rates of ACPA-positive and ACPA-negative patients.24 Other studies have suggested that positive RF and ACPA titers can predict an inadequate response to anti-TNF-α therapy,25,26 whereas others reported inconsistent and contradictory conclusions.27–29

Rheumatoid vasculitis is an uncommon but severe manifestation of RA that represents a more aggressive form of the disease and influences the treatment approach. A previous study found that patients who were refractory to at least three bDMARDs or two bDMARDs with different mechanism of action had a higher prevalence of extra-articular manifestations, including vasculitis.30 This corroborates the findings of this study, supporting the idea that vasculitis can be associated with a higher switch rate of bDMARDs. However, it is important to note that the number of patients with rheumatoid vasculitis in this study is small, and therefore, conclusions draw from these results should be interpreted with caution.

Smoking has long been recognized as one of the most important extrinsic risk factors for the development and severity of RA.31,32 Previous literature suggests that patients treated with anti-TNF-α agents who are smokers tend to experience poorer treatment response and drug survival.33–36 One the other hand, smokers treated with rituximab and tocilizumab did not seem to have a worse response to therapy.37,38

Furthermore, a prior study involving patients with RA who started their first bDMARD revealed a significantly higher rate of switching in the first year of treatment among those with a history of depression.39 Additionally, other study that included patients with RA, psoriatic arthritis and axial spondyloarthritis who received bDMARDs over a 2-year period found that the switching was associated with the use of antidepressant and anxiolytic medications.40

Tobacco exposure and depression appear to be modifiable risk factors associated with early switching due to ineffectiveness in patients with RA. These findings underscore the importance of addressing these factors in daily clinical practice to enhance the overall response to therapy and the well-being of patients.

To optimize treatment outcomes, it is imperative to reinforce the importance of smoking cessation in patients with RA. Healthcare providers should engage patients in discussions about quitting smoking and offer effective interventions and support to facilitate smoking cessation.

Depression, another factor linked to early switching due to ineffectiveness in this study, is often underdiagnosed and undertreated in patients with RA.41 To improve patient outcomes, routine screening for depression should be integrated into daily clinical practice of RA management. Identifying and addressing depression early on can have a positive impact not only on the patient's emotional well-being, but also on their ability to manage their illness and on the treatment response.

Some limitations of this study should be acknowledged. Major limitations are related to the single-center retrospective nature of the study and the extended study duration that may interfered with the outcome. Additionally, the small number of patients treated with abatacept may limit the conclusions about the switching rate due to ineffectiveness of this drug.

To our knowledge, this is the first study that identifies specific baseline features as possible predictors of switching due to ineffectiveness in the first year of treatment in a Portuguese cohort of RA patients.

None to declare.