FormalPara Key Summary Points

Why carry out this study?

Upadacitinib is United States Food and Drug administration (FDA) approved and has demonstrated efficacy in the management of rheumatoid arthritis (RA).

However, there is a lack of long-term data in clinical practice on upadacitinib treatment response and in comparison to other standard of care therapies among patients with RA.

What was learned from the study?

In the first 12 months of treatment, patients with RA initiating upadacitinib were significantly more likely to be adherent and less likely to discontinue treatment, compared with patients who initiated adalimumab, baricitinib, and tofacitinib, regardless of tumor necrosis factor inhibitor (TNFi) experience.

The results of this study illustrate the potential benefit of initiating upadacitinib compared with other Janus kinase inhibitors and standard of care therapies, including following recent discontinuation of a TNFi.

Introduction

Disease-modifying anti-rheumatic drugs (DMARDs) have made rheumatoid arthritis (RA) a more manageable disease by targeting inflammation, improving disease signs and symptoms, and preventing further joint damage [1]. Both the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) guidelines recommend a treat-to-target approach, with the preferred treatment target of remission, or, when this is not possible, low disease activity [2,3,4]. If there is no improvement within 3 months of treatment initiation or the treatment target is not reached by 6 months, then the ACR and EULAR guidelines recommend changing to a medication with an alternate mechanism of action (MoA) (“switching”) [2, 4].

Treatment for RA is typically initiated with conventional synthetic DMARDs (csDMARDs; includes methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine). When csDMARDs are unsuccessful as a first-line treatment, biologic DMARDs [bDMARDs; includes tumor necrosis factor inhibitors (TNFi), IL-6 inhibitors, T-cell costimulatory blocking agents] and more novel targeted synthetic DMARDs [tsDMARDs; includes JAK inhibitors (JAKi)] are recommended [2]. Approximately 68–77% of patients receive a TNFi as a first line bDMARD [5, 6]. However, findings suggest that approximately two-thirds of patients receiving TNFi treatment as their first biologic do not reach therapy targets within 6 months [5, 7]. In addition to poorer patient outcomes, not achieving RA treatment targets such as remission has been associated with significantly greater health care costs compared to achieving these targets, with the cost of care rising with increasing disease activity [8, 9]. Further, despite guidelines recommending switching to an alternative MOA when treatment targets are not achieved, prior studies have demonstrated that 54.2–63.5% of patients switch to a second TNFi after discontinuing a first-line TNFi [10, 11].

Upadacitinib, an oral JAKi, was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with moderately to severely active RA [6]. Upadacitinib has demonstrated greater clinical efficacy versus placebo, methotrexate, and adalimumab in patients refractory to csDMARDs or methotrexate, and versus placebo and abatacept in patients with an inadequate response to bDMARD [12,13,14,15,16]. However, long-term data on upadacitinib’s effectiveness in clinical practice versus standard of care treatments such as adalimumab, a commonly used TNFi, and baricitinib and tofacitinib, other JAKi, are still limited.

As long-term clinical effectiveness data from sources such as registries and electronic health records can take substantial time to accumulate for newly approved treatments, large administrative claims sources are well suited for evaluating other relevant patient outcomes, such as adherence and persistence for new therapies [17]. Medication adherence and persistence outcomes may serve as useful proxies for treatment effectiveness and tolerance to inform treatment decisions before long-term, real-world clinical outcomes data become available [18, 19]. Both adherence and persistence with RA medication have been shown to be important factors that can help drive achievement of treatment goals [20,21,22]. Additionally, nonadherence has been associated with increased health care costs, which may be burdensome for both patients and the health care system [23].

Research determining how newer therapies, such as upadacitinib, compare to other treatments within the same class (i.e., JAKi) and to well-established standard-of-care therapies (e.g., TNFi) in clinical practice may help guide treatment decision-making for physicians and patients. The aim of this study was to assess 12-month adherence and persistence among patients with RA in clinical practice receiving upadacitinib, adalimumab, baricitinib, or tofacitinib.

Methods

Study Design and Patients

This retrospective cohort study included eligible adults (aged ≥ 18 years) with ≥ 1 RA diagnosis [International Classification of Diseases 10th Revision (ICD-10) codes: M05.x, M06.x] from January 1, 2018 to January 31, 2022 in the Merative™ MarketScan® Research Databases [24], including Commercial and Medicare supplemental claims databases. Patients were required to have ≥ 1 pharmacy claim for upadacitinib, adalimumab, baricitinib, or tofacitinib. The index date was defined as the date of the first pharmacy claim for upadacitinib (on or after August 19, 2019; date of US FDA approval), adalimumab, baricitinib, or tofacitinib (all on or after January 1, 2019) with ≥ 12 months of continuous insurance enrollment pre- and post-index.

Outcomes

Baseline characteristics included age, gender, Charlson Comorbidity Index (CCI) score, payer type, the percentage of patients using targeted immunomodulates (TIMs) during the baseline period (defined as the 12-month period before the index date) and at any time before the index date, and the percentage of patients with previous TNFi experience during the baseline period and at any time before the index date.

Treatment adherence and persistence outcomes were assessed at 12 months post-index. Treatment adherence was assessed using the proportion of days covered (PDC) [25], defined as the total number of days that the patient had access to the index medication during the post-index period divided by the total length of the post-index period (i.e., 12 months). Median PDC and the proportion of patients considered adherent to treatment (PDC ≥ 80%) [25] were evaluated. Discontinuation outcomes included the proportion of patients discontinuing treatment by 12 months and the time to treatment discontinuation. Treatment discontinuation was defined as a gap of ≥ 60 days between pharmacy claims for the index medication.

All of the above outcomes were also evaluated in the subgroup of patients with prior TNFi use in the 12-month pre-index (i.e., baseline) period.

Statistical Analyses

Demographics and characteristics were presented as descriptive statistics reporting the number and percentage of patients for categorical outcomes or mean ± standard deviation (SD) for continuous outcomes. The median PDC [interquartile range (IQR)], the percentage of patients who were adherent to treatment, the percentage of patients who discontinued treatment, and the mean ± SD time to discontinuation were reported. Adjusted odds ratios (OR) and 95% confidence intervals (CI) for PDC ≥ 80% were determined by logistic regression, and adjusted hazard ratios (HR) and 95% CI for treatment discontinuation were determined by a Cox proportional hazard model. All analyses were adjusted for age, sex, CCI score, payer type, and TIM experience during baseline.

Subgroup analyses of patients with TNFi use in the 12-month pre-index period were adjusted for age, sex, CCI score, and payer type at baseline. p < 0.05 was considered statistically significant. All analyses were performed using the Instant Health Data (IHD) software (Panalgo, Boston, MA, USA) and R version 3.2.1 ® Foundation for Statistical Computing, Vienna, Austria).

Ethical Requirements

Through a paid contract with Merative™ MarketScan® Research Databases [24], authors were granted permission to use and provided access to the database. The authors affirm that this retrospective database analysis did not collect, use, or transmit patient-identifiable data. The study is compliant with data security requirements of the Health Insurance Portability and Accountability Act of 1996.

Results

Study Population

A total of 6317 patients were included, 683 who initiated upadacitinib, 3732 adalimumab, 132 baricitinib, and 1770 tofacitinib (Fig. 1). Most patients were female (76.0–86.4%) with a mean ± age of 49.7 ± 10.8 to 52.2 ± 9.5 (Table 1). Of patients who initiated upadacitinib, 65.7% (n = 449) had TIM use (included index medications, plus abatacept, certolizumab, etanercept, infliximab, golimumab, tocilizumab, rituximab, and sarilumab) any time before the index date compared with 30.8% (n = 1150) of patients who initiated adalimumab, 87.1% (n = 115), who initiated baricitinib, and 66.6% (n = 1178) who initiated tofacitinib. Of patients who initiated upadacitinib, 32.4% (n = 221) had used a TNFi in the 12 months baseline period compared with 19.0% (n = 710) of patients who initiated adalimumab, 34.9% (n = 46) who initiated baricitinib, and 35.6% (n = 630) who initiated tofacitinib.

Fig. 1
figure 1

Patient attrition. FDA US Food and Drug Administration, RA rheumatoid arthritis.aOn or after August 19, 2019 for upadacitinib (US FDA approval date)bBaseline defined as the 12-month pre-index period

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Table 1 Baseline patient demographic and clinical characteristics
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Medication Adherence

Among all assessed treatments, median PDC at 12 months was greater for patients initiating upadacitinib [median PDC (IQR) = 0.81 (0.41–0.95)] compared with patients who initiated adalimumab [median PDC (IQR) = 0.75 (0.38–0.96)], baricitinib [median PDC (IQR) = 0.58 (0.25–0.86)], and tofacitinib [median PDC (IQR) = 0.72 (0.33–0.92)]. A significantly greater proportion of upadacitinib-treated patients (50.8%) were adherent to treatment (PDC ≥ 80%) compared with patients initiating adalimumab [45.5%; adjusted OR (95% CI): 0.82 (0.69, 0.96)], baricitinib [31.8%; adjusted OR (95% CI): 0.46 (0.31, 0.68)], and tofacitinib [43.2%; adjusted OR (95% CI): 0.74 (0.62, 0.88)] (all p < 0.05; Fig. 2a and b).

Fig. 2
figure 2

Proportion of patients with PDC ≥ 80% and likelihood of adherence at 12 months in all initiators and TNFi-experienced patients treated with UPA versus ADA, BARI, and TOFA. ADA adalimumab, BARI baricitinib, CI confidence interval, PDC proportion of days covered, TNFi tumor necrosis factor inhibitor, TOFA tofacitinib, UPA upadacitinib. *p < 0.05, **p < 0.01, ***p < 0.001

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In patients with prior TNFi use in the baseline period, median PDC at 12 months was greater with upadacitinib [median PDC (IQR) = 0.82 (0.42–0.94)] versus adalimumab [median PDC (IQR) = 0.69 (0.31–0.95)], baricitinib [median PDC (IQR) = 0.58 (0.33–0.84)], and tofacitinib [median PDC (IQR) = 0.74 (0.33–0.93)]. Patients initiating upadacitinib (54.3%) were significantly more likely to be treatment-adherent than those initiating adalimumab [42.3%; adjusted OR (95% CI): 0.63 (0.46, 0.85)], baricitinib [30.4%; adjusted OR (95% CI): 0.36 (0.18, 0.72)], and tofacitinib [44.8%; adjusted OR (95% CI): 0.67 (0.49, 0.92)] (all p < 0.05; Fig. 2c and d).

Treatment Persistence

Among all initiators, fewer upadacitinib-treated patients (45.4%) discontinued treatment at 12 months versus patients treated with adalimumab (50.4%), baricitinib (59.9%), and tofacitinib (52.0%) (Fig. 3a). Risk of treatment discontinuation was significantly higher in patients treated with adalimumab [adjusted HR (95% CI): 1.14 (1.01, 1.29)], baricitinib [adjusted HR (95% CI): 1.48 (1.16, 1.90)], and tofacitinib [adjusted HR (95% CI): 1.22 (1.07, 1.38)] compared with upadacitinib (all p < 0.05; Fig. 3b; Supplementary Fig. 1). The mean ± SD time to discontinuation was 256.4 ± 127.8 (upadacitinib), 248.6 ± 124.6 (adalimumab), 221.1 ± 132.2 (baricitinib), and 238.5 ± 131.0 (tofacitinib) days.

Fig. 3
figure 3

Proportion of all initiators and TNFi-experienced patients discontinuing treatment and the risk of discontinuation for UPA versus ADA, BARI, and TOFA. ADA adalimumab, BARI baricitinib, CI confidence interval, TNFi tumor necrosis factor inhibitor, TOFA tofacitinib, UPA upadacitinib. *p < 0.05; **p < 0.01

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In patients with TNFi experience during the baseline period, a lower proportion of patients treated with upadacitinib (42.5%) discontinued treatment at 12 months compared with patients treated with adalimumab (53.0%), baricitinib (63.0%), and tofacitinib (51.6%) (Fig. 3c). The risk of treatment discontinuation was significantly higher in adalimumab [adjusted HR (95% CI): 1.35 (1.07, 1.69)], baricitinib [adjusted HR (95% CI): 1.73 (1.14, 2.62)], and tofacitinib-treated patients [adjusted HR (95% CI): 1.35 (1.07, 1.70)] versus upadacitinib-treated patients (all p < 0.05; Fig. 3d, Supplementary Fig. 2). The mean ± SD time to discontinuation was 267.6 ± 122.9 (upadacitinib), 241.5 ± 123.7 (adalimumab), 223.0 ± 122.5 (baricitinib), and 240.2 ± 131.6 (tofacitinib) days.

Discussion

The results of this retrospective analysis demonstrated that, in the first 12 months of treatment, RA patients initiating upadacitinib were more likely to be adherent compared with adalimumab-, baricitinib-, and tofacitinib-treated patients, regardless of recent prior TNFi use. With regard to persistence, patients treated with adalimumab, baricitinib, and tofacitinib were more likely to discontinue treatment by 12 months regardless of recent TNFi experience compared with upadacitinib initiators. Additionally, differences between upadacitinib and adalimumab, baricitinib, and tofacitinib appear to be larger in the TNFi-experienced subgroup, compared with all initiators.

Following the approval of upadacitinib in 2019, this is one of the first studies in the US evaluating medication adherence and persistence within the Janus kinase (JAK) class and compared with the standard of care in RA. In the current study, the proportion of patients discontinuing treatment was lowest for upadacitinib-treated patients (45.4%), followed by adalimumab (50.4%), tofacitinib (52.0%), and baricitinib (59.9%). This corresponds to persistence rates of 54.6% for upadacitinib-treated patients compared with 49.6%, 48.0%, and 40.1% for adalimumab, tofacitinib, and baricitinib at 12 months, respectively. Results of a recent retrospective observational study [26] in Australian patients on first- and second-line treatments are supportive of the results in the present study. In the Australian study, persistence rates at 12 months were 78% for upadacitinib-treated patients compared with 54%, 55%, and 64% for tofacitinib, adalimumab, and baricitinib, respectively; overall, JAKi persistence rates were superior to TNFi [26]. Findings from both studies indicate that treatment discontinuation rates are lower and persistence rates are greater for upadacitinib-treated patients than those treated with another JAKi or adalimumab.

Data from a specialty pharmacy claims database found that patients on first-line bDMARD or tsDMARD, where 75% were receiving TNFi and 25% other MoA [including JAKi, interleukin (IL)-6 inhibitors, T-cell inhibitors, and IL-1 inhibitors], the median PDC was 0.94 and nonpersistence was 27% [22]. Findings from another US-based claims database showed that PDC (mean ± SD) was 0.55 ± 0.30 for tofacitinib-treated patients and 0.57 ± 0.30 for adalimumab-treated patients [27]. Additionally, a systematic literature review of US-based studies found that the proportion of patients who adhered to adalimumab ranged from 21 to 70%, compared with 45.5% in the current study [19]. This illustrates that there is variability in findings presented in adherence and persistence research within the literature and between the current study and other research. The variability could be related to various treatments included in other studies, differences in study design or claims data, or varying definitions or measurements of adherence and persistence, all of which make it challenging to compare outcomes across studies.

In this study, differences in adherence and persistence between upadacitinib-treated patients and adalimumab-, tofacitinib-, and baricitinib-treated patients were generally larger in the TNFi-experienced group than for all initiators. For upadacitinib compared with adalimumab, this may be at least partly due to the all-initiators group including more first-line initiators of adalimumab compared to first-line initiators of upadacitinib. In other real-world research, patients have demonstrated better clinical outcomes and retention on first-line versus second-line adalimumab [28, 29]. Therefore, TNFi-experienced patients on adalimumab may be more likely to discontinue than patients on their first line of treatment. Additionally, for TNFi-experienced patients, worse results for adalimumab might suggest that there is a poorer response to TNFi cycling compared to switching to a treatment with a new MoA [30].

Approximately 30–40% of patients with RA do not respond to TNFi treatment [31]. This includes patients who initially respond and then lose the response over time, as well as those who have untoward side effects [31]. Following a TNFi discontinuation, patients may “switch” to a different MoA or “cycle” to another TNFi [31]. The ACR guidelines for the treatment of RA recommend switching to a bDMARD of a different MoA or to a tsDMARD, such as a JAKi, instead of cycling through a second TNFi [2]. Clinical trial data have demonstrated that patients with RA who fail TNFi treatment can achieve efficacy responses over 24 weeks with upadacitinib [32]. The findings of one phase 3 trial showed significant improvements in ACR 20 improvement criteria (ACR20) and Disease Activity Score for 28 joints (DAS28) at Week 12 in upadacitinib versus placebo-treated patients with RA who had an inadequate response to bDMARDs [14]. Additionally, in the SELECT-COMPARE study, a significant number of patients who were rescued to upadacitinib after an inadequate response to adalimumab achieved clinically meaningful responses up to Week 48 [33]. Together with the results of the present study, this suggests that treatment with upadacitinib is effective and that there is less risk of discontinuation, compared with adalimumab, tofacitinib, and baricitinib, in TNFi-experienced patients with RA.

Early persistence and increased treatment adherence have been shown to help patients reach RA treatment targets, such as low disease activity or remission [20, 21]. A cross-sectional survey of patients with RA showed that approximately three-quarters of patients are not satisfied with their current treatments, including bDMARDs, and 44% continue to experience flare-ups and debilitating symptoms, such as fatigue and pain [34]. Patients reported that these bothersome symptoms have a moderate-to-severe impact on their life, and a third of patients felt that there were not enough medication options available to them [34]. The findings of this study support the use of upadacitinib as a treatment alternative for patients with RA, regardless of their prior experience on TNFi, which historically may have been more difficult to treat [35]. Future real-world comparative effectiveness research evaluating clinical and patient-reported outcomes is warranted to supplement the findings of this study. Furthermore, research evaluating whether the adherence and persistence outcomes observed in this study are sustained over longer periods, and the relationship between these outcomes and clinical and patient-reported effectiveness, may further support the use of adherence and persistence data as a valid proxy for clinical effectiveness when new therapies are introduced to the market.

Limitations

While data on patients with RA from a claims database may be more representative of the patient population than findings from a clinical trial, a limitation of the study is that claims data may not be generalizable to the wider population of patients with RA, such as those covered by Medicare. There are limitations inherent in using claims data, in that the data may be incomplete, inaccurate, or missing. Additionally, pharmacy claims reflect that the prescription was filled and the medication was picked up from the pharmacy; however, we cannot guarantee that the patient actually took the medication as prescribed. Specific to this study, the analysis did not observe and adjust for factors that could be driving treatment adherence and persistence, such as drug-related adverse effects, baseline disease severity, number of previous RA advanced therapies, time since initial RA diagnosis, treatment effectiveness, and social determinants of health. Finally, this analysis may not fully account for channeling bias, whereby treatments are prescribed based on the patient’s condition or prognosis at the time of prescribing.

Conclusion

In the first 12 months of treatment, patients with RA initiating upadacitinib were significantly more likely to be adherent and less likely to discontinue treatment compared to patients who initiated adalimumab, baricitinib, and tofacitinib. Differences for upadacitinib versus adalimumab, baricitinib, and tofacitinib were similar or further improved in patients with recent TNFi experience. These data highlight the potential benefit of initiating upadacitinib compared to other JAKi and standard of care therapies, including after recent discontinuation of a TNFi. Future research evaluating comparative real-world clinical and patient-reported outcomes among these RA therapies and the association between adherence and persistence and these outcomes is warranted.