Treatment Persistence and Clinical Outcomes of Tumor Necrosis Factor Inhibitor Cycling or Switching to a New Mechanism of Action Therapy: Real-world Observational Study of Rheumatoid Arthritis Patients in the United States with Prior Tumor Necrosis Factor Inhibitor Therapy

Approximately 1.5 million US adults have rheumatoid arthritis (RA) [1]. The total annual societal cost of RA in the US is estimated to be approximately $39 billion, including $8 billion of direct healthcare costs, $11 billion of indirect healthcare costs such as work and productivity loss, and $20 billion of intangible costs such as decreased quality of life and premature mortality [2].

RA is a chronic, inflammatory, autoimmune disease characterized by joint swelling, tenderness, and destruction [3]. Conventional synthetic disease-modifying antirheumatic drugs (cDMARDs), including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, are the standard of care for RA [4‐6]. Treatment with a tumor necrosis factor inhibitor (TNFi), such as adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab, or other biologic agents and small molecules is recommended for RA patients with moderate or high disease activity despite treatment with one or more cDMARDs [6]. However, many RA patients do not benefit from or tolerate the initial TNFi therapy, or they lose response over time [7, 8]. Several trials and observational studies have reported that clinical outcomes may improve after patients switch to either another TNFi (TNFi cycling) or to a therapy with a new mechanism of action (new MOA switching) such as abatacept, anakinra, rituximab, tocilizumab, or tofacitinib [9‐18]. Recent changes in the American College of Rheumatology’s RA treatment guidelines now give new MOA therapies the same priority as TNFi when selecting therapy in patients with established disease [6].

TNFi cycling is a common occurrence in clinical practice [18‐25], but the clinical outcomes of TNFi cycling or new MOA switching are not clearly understood. The objectives of this study were to compare treatment persistence and clinical outcomes associated with TNFi cycling vs. new MOA switching in a real-world setting.

The use of anti-TNF agents has revolutionized rheumatology, yet the patterns of use and rationale for cycling or switching have not been well defined. TNFi cycling may restore clinical benefits after loss of response to the first TNFi [31], and the response to TNFi cycling is greater among patients with secondary loss of efficacy than those with primary lack of response to the initial TNFi [32]. However, fewer than half of patients achieve a significant clinical response after cycling to a second TNFi, and clinical benefits generally become negligible after cycling to a third TNFi [33]. It is important, therefore, to understand whether new MOA switching offers benefits compared with TNFi cycling.

In this study, new MOA switchers were significantly more likely than TNFi cyclers to persist on the study index drug and significantly less likely to switch to another drug after having switched to the study index drug. This analysis did not specify a minimum duration of follow-up post-index, but the median follow-up was approximately 30 months and approximately 85% of patients provided at least 1 year of follow-up data for treatment patterns. In this subgroup, the 1-year persistence rate was significantly greater in the new MOA switching cohort, and the 1-year switching rate was significantly greater in the TNFi cycling cohort. These results were generally consistent with a previous report that treatment persistence was better for switchers to new MOA therapy (abatacept, rituximab, or tocilizumab) compared with TNFi cyclers [23]. A second study reported that switching to the new MOA therapy tocilizumab or cycling to the TNFi etanercept was associated with better treatment persistence than cycling to adalimumab or infliximab [34]. A third study reported similar treatment persistence rates among patients who cycled to etanercept or switched to the new MOA therapies abatacept or tocilizumab; treatment persistence for other TNFi such as adalimumab or infliximab was not evaluated [17]. A fourth study reported significantly greater treatment persistence after switching to the new MOA DMARDs rituximab or tocilizumab compared with TNFi cycling [35].

Better treatment persistence is associated with better treatment outcomes in RA [36‐38], so this analysis also examined clinical outcomes in each cohort. Interventional comparative effectiveness studies are lacking, but observational studies have reported that new MOA switching may be more effective than TNFi cycling. Analyses of 1328 patients in the British Society for Rheumatology Biologics Register [13], the MIRAR study of 1124 patients [14], and the SWITCH-RA study of 728 patients with RA [15] each reported that switching from a TNFi to rituximab was associated with better clinical outcomes than TNFi cycling. A systematic review and Bayesian analysis of published studies determined that switching to a new MOA therapy (abatacept, rituximab, or tocilizumab) was more effective than TNFi cycling in RA patients with an inadequate response to the initial TNFi [39]. Similar results were observed in this study, which expanded upon the previous analyses to include a larger set of new MOA therapies, including abatacept, anakinra, rituximab, tocilizumab, and tofacitinib. This study also built upon existing literature by examining both treatment persistence and clinical outcomes within the same population.

In the bivariate analysis, compared with TNFi cycling, patients who switched to a new MOA therapy had substantially greater reductions from baseline for CDAI, DAS28-ESR, and DAS28-CRP. Patients who switched to a new MOA therapy also were more likely than TNFi cyclers to achieve a clinically important reduction in CDAI from baseline. However, after adjusting for baseline CDAI, clinical outcomes continued to favor new MOA switchers but the differences from TNFi cyclers were no longer statistically significant. New MOA switchers also had more severe disease activity at baseline, which may have allowed for greater improvement. An advantage of this analysis was the ability to examine the timing of treatment discontinuation with precision, because physicians reported treatment discontinuation prospectively in JointMan instead of being estimated from treatment gaps, which is a standard approach in retrospective claims-based analyses of treatment patterns [40, 41]. JointMan also collected information about the reason for discontinuation of the prior therapy, which cannot be evaluated in claims databases. Significant differences between the cohorts also were observed at baseline for the reported reason for discontinuing the prior TNFi, such as secondary loss of efficacy or adverse events. However, when these reasons were added to the generalized linear model in a post hoc sensitivity analysis, reasons for discontinuation of the prior TNFi did not significantly predict clinical outcomes. In addition, the sample size may have contributed to the inability to detect statistically significant differences in clinical outcomes between the cohorts. A post hoc power analysis based on the actual number of patients that were evaluable for mean change in CDAI showed that the power was <65% to detect a difference of 3 units for CDAI, assuming a common standard deviation of 13.7 and using a two-group t test with a 0.05 two-sided significance level.

In this real-world study, more than half of the patients cycled to another TNFi instead of switching from a TNFi to a new MOA. This finding was consistent with several previous studies that reported higher rates of TNFi cycling than new MOA switching in clinical practice [18‐25]. Clinicians reported that they were as likely to cycle the patient to another TNFi or switch to a new MOA when the patient had primary ineffectiveness (i.e., they never reached the therapeutic goal with the prior TNFi) and they were significantly more likely to cycle to another TNFi than to switch to a new MOA after secondary loss of efficacy for the prior TNFi. This therapeutic strategy is contrary to evidence from previous studies, which showed that when the reason for stopping the prior TNFi is primary ineffectiveness, a second TNFi is more likely to be ineffective as well [42] and switching to a new MOA is significantly more effective than TNFi cycling in these patients [18]. Thus, there is a need for increased awareness in clinical practice that switching to a new MOA instead of TNFi cycling may be particularly beneficial among patients who stop the prior TNFi because of ineffectiveness. This may be particularly relevant for real-world clinical practice based on the finding that most patients in this study (more than 60%) switched therapy due to either primary or secondary ineffectiveness of the prior TNFi.

Incomplete data entry by providers at some patient encounters may have influenced the analysis. Approximately one in four patients with at least one follow-up visit did not have CDAI reported both at baseline and within 12 months post-index. The number of patients with missing data was greater for DAS28-ESR and DAS28-CRP, which require additional laboratory tests that may not be ordered at every visit. JointMan focuses on the treatment and outcomes of rheumatoid arthritis at rheumatology visits; thus, non-rheumatology conditions (e.g., hypertension, hyperlipidemia) and non-rheumatology medications were not reported consistently in the database and could not be reliably analyzed. Although both academic centers and non-academic practices were represented, the JointMan US clinical database included outpatients treated at participating sites in a limited number of geographic regions that may not reflect the nationwide distribution of locations where RA patients receive treatment. Multivariable analysis adjusted for known patient characteristics that could have influenced treatment persistence or clinical outcomes, but other factors not reported in the JointMan database may have contributed to the study findings. Finally, this analysis was based on broad categories of TNFi or new MOA DMARDs, but individual therapies within the new MOA cohort may have an unequal response. A much larger sample size would be required to detect clinically meaningful differences among individual therapies.

In this real-world analysis of patients with RA who discontinued their prior TNFi, switching to a new MOA DMARD was associated with significantly better treatment persistence than cycling to another TNFi. New MOA switchers also had greater improvement in disease activity than TNFi cyclers, but the difference was not statistically significant after adjusting for baseline disease activity. This study suggests that a more evidence-based approach to switching therapy versus cycling is needed in the management of patients with RA.