Background
Patients with rheumatoid arthritis (RA) experience progressive and significant restrictions in daily living and frequently report pain, fatigue, sleep disturbances, and functional impairment in work and leisure-time physical activities [
1‐
3]. Patient-reported symptoms are generally present early in the disease, and, when present, can be a significant burden on patients’ quality of life. The American College of Rheumatology (ACR) established a core set of measures to assess disease activity in clinical trials, which includes several patient-reported outcomes (PROs) associated with RA [
4]. Additional PROs for use in clinical trials have been suggested by Outcome Measures in Rheumatology Clinical Trials (OMERACT) [
5]. The ACR and the European League Against Rheumatism (EULAR) have recognized PROs as important factors in the assessment of patient disease activity and have recommended the evaluation of PROs in daily clinical practice when considering response to therapy [
6,
7]. Regulatory authorities have recommended that PROs be used as additional measures of effectiveness in clinical trials of RA [
8].
Treatment recommendations for RA highlight the importance of early diagnosis and of intensive treatment strategies, with the target of remission or lowest possible disease activity [
9]. The treatment regimen for RA suggested by the ACR and EULAR includes initial conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), especially methotrexate (MTX); if not effective, combining csDMARDs with biological DMARDs (bDMARDs), or oral targeted synthetic DMARDs (tsDMARDs) that target the intracellular Janus kinase (JAK) pathways, are recommended [
6,
7]. This early intensive disease management has been shown to mitigate joint damage and inflammation, to avoid disability from RA, and to improve patient health-related quality of life [
10‐
13].
It has been advocated that the treatment of RA should be a shared decision-making process between the patient and the physician [
9]. Together, they must address questions of significance to the patients, including the potential improvement of PROs [
9]. A relevant question to both patients and physicians is whether bDMARDs or tsDMARDs require co-administration of methotrexate (MTX), which itself is associated with potential adverse effects that may affect patient function (fatigue, nausea, etc.) [
14,
15].
Baricitinib is a selective JAK1 and JAK2 inhibitor that was recently approved for the treatment of moderately to severely active RA in adults in the European Union and is under development for RA in other regions. Baricitinib interferes with pathways that are believed to be important in the pathogenesis of RA. RA-BEGIN was a phase III study (NCT01711359) conducted in patients with active RA who were naïve to csDMARDs (no or limited exposure to MTX) or bDMARDs. Baricitinib alone or in combination with MTX demonstrated superior clinical efficacy with acceptable safety compared to MTX as the initial therapy for patients with active RA [
1]. In the present analysis of the RA-BEGIN study, we report the effects of baricitinib, administered as monotherapy or in combination with MTX compared to MTX monotherapy, on the PRO measures.
Methods
Patients
Full details regarding the primary efficacy and safety outcomes of this study have been reported previously [
1]. In summary, patients were ≥ 18 years old with moderately to severely active RA (≥6/68 tender and ≥ 6/66 swollen joints; high-sensitivity C-reactive protein ≥ 3.6 mg/L (upper limit of normal 3.0 mg/L); seropositive for rheumatoid factor or anti-citrullinated peptide antibodies) and naïve (or had no more than three prior doses of MTX) to DMARDs.
Study protocol and oversight
RA-BEGIN was a randomized, 52-week, double-blind, active comparator-controlled study conducted in 18 countries. Patients were randomized 4:3:4 to receive oral MTX monotherapy (administered orally once weekly), baricitinib monotherapy (4 mg once daily (QD)), or the combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX). Methotrexate was initiated at 10 mg/week and, if tolerated, increased to 20 mg/week by week 8. A lower dose of MTX was available for patients in whom a lower dose was clinically indicated or required by national guidelines (initial dose of 7.5 mg and a maximum dose of 12.5 mg). Rescue treatment (baricitinib + MTX) was available, beginning at week 24, for those patients whose tender and swollen joint counts did not improve by ≥ 20% from baseline. The study was conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by each center’s institutional review board or ethics committee. All patients provided written informed consent.
Patient-reported outcomes
Pre-specified secondary PROs were included in the study. The Patient’s Global Assessment of Disease Activity (PtGA) and the patient’s assessment of pain were evaluated using visual analog scales (VAS) of 0–100 mm. Physical function was assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) [
2,
3]; scores range from 0 to 3, with lower scores reflecting better physical function and less disability. An HAQ-DI score of ≤ 0.25 is considered the normative value and an improvement of ≥ 0.22 has been shown to be the minimum clinically important difference (MCID) [
16,
17]. Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale; scores range from 0 to 52, with higher scores representing less fatigue; in this study a value of 3.56 was used for the MCID [
18‐
20]. Duration of morning joint stiffness (MJS) was reported by the patient as the length of time in minutes that MJS lasted on the day prior to each study visit. The patients’ assessments of the worst joint pain and the worst tiredness over the past 24 hours were measured using novel Worst Joint Pain and Worst Tiredness Numeric Rating Scales (NRS). Scores for both the NRSs range from 0 (no joint pain/tiredness) to 10 (“as bad as you can imagine”).
Health-related quality of life (HRQOL) was evaluated using the Medical Outcomes Study (MOS) Short Form-36 (SF-36; version 2, Acute) [
21,
22], which assesses eight domains scored from 0 to 100 that can be aggregated into physical and mental component scores (PCS, MCS) and compared to values from normal individuals. An MCID change of 5 was used to assess the clinical relevance of changes in SF-36 component scores [
23,
24]. The EuroQol 5-Dimensions (EQ-5D) Health State Profile was also used to assess HRQOL. The EQ-5D consists of two components: a descriptive system of the respondent’s health and a rating of their current state (0 − 100 mm VAS) [
25]. The UK and US scoring algorithms provide an index score using the UK or US population weighting normalized to that population [
25‐
27].
The Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) instrument was used to measure overall work productivity and impairment of regular activities during the past 7 days. Scores are calculated as impairment percentages [
28], with higher percentages indicating greater work and activity impairment and less productivity.
The PROs were assessed at baseline, week 1, week 2, week 4, and every 4 weeks thereafter to week 24; after week 24 they were assessed at weeks 32, 40, and 52; with the exception of the FACIT-F, which was assessed at baseline, week 1, week 4 and then followed the same schedule as the other PROs and the SF-36, EQ-5D, and WPAI-RA, which were assessed at baseline and week 4 and then followed the same schedule as the other PROs.
Statistical analysis
Randomized patients were included in the analyses under a modified intention-to-treat principle (mITT analysis set), which included all patients treated with ≥ 1 dose of study drug. Treatment comparisons for categorical and continuous measures were performed using logistic regression and analysis of covariance (ANCOVA), respectively, with baseline value (for continuous measures only), treatment, geographical region, and presence of baseline joint erosions (yes/no) in the model. The Fisher exact test was used for categorical data when sample size requirements for the logistic regression model were not met (< 5 responders in any category for any factor). Differences in the duration of MJS were assessed with the Wilcoxon rank sum test. Any duration of MJS lasting > 12 hours was truncated to 720 minutes for the purpose of this analysis.
Patients who were rescued or discontinued from the study or study treatment were thereafter defined as non-responders (non-responder imputation (NRI)) for all categorical data. These patients also had their last observations before rescue or discontinuation (modified last observation carried forward (mLOCF)) used for analyses of continuous data. The WPAI-RA analyses were censored after rescue or study discontinuation without imputation applied.
Discussion
The primary objective of the RA-BEGIN study was to evaluate baricitinib, an oral tsDMARD that selectively inhibits JAK1 and JAK2, as monotherapy or combined with MTX compared to MTX monotherapy in patients with active RA and no prior DMARD therapy or limited prior MTX therapy. The current analysis has focused on PROs which, in conjunction with clinical assessment measures, are a valuable and practical tool for comprehensive disease management and provide important insights into the patient’s response to therapy and as such, should be utilized in the clinic [
29]. Although MTX was effective in this population, particularly at later time points, the majority of the pre-specified PROs of physical function, HRQOL, PtGA, pain, fatigue, duration of MJS, tiredness, and joint pain were all statistically significantly improved to a greater extent at many or all time points in patients treated with baricitinib monotherapy and baricitinib + MTX compared to the MTX monotherapy.
The clinical relevance of these PRO improvements with baricitinib is emphasized by their consistent superiority to MTX, the oral standard of care in the treatment of RA, in contrast to simply being compared to a placebo control. The ACR guidelines and EULAR recommendations propose that MTX be the first-line DMARD treatment for DMARD-naïve patients because of its effectiveness in controlling disease activity, improving patient function and limiting radiographic progression in up to one third of patients, and having an acceptable and well-known safety profile and a low cost [
1,
6,
7]. These recommendations have relied on studies in MTX-naïve patients that compared MTX to bDMARD monotherapy and indicated that MTX was as clinically effective (including PRO data) as bDMARD monotherapy [
30‐
32]. One study, TEMPO, used a similar design to RA-BEGIN to compare etanercept either as monotherapy or in combination with MTX vs. MTX in patients with mean disease duration of over 6 years. In TEMPO, etanercept monotherapy had similar benefit to MTX monotherapy in improving PROs [
33].
There are, however, a number of patients for whom MTX monotherapy is unsuitable. There is, therefore, an unmet need for alternative therapeutic choices for such patients; novel, orally administered tsDMARDs, such as baricitinib, would appear to have desirable attributes in this setting. Importantly, in RA-BEGIN, the comparable effects on PRO improvements in the baricitinib monotherapy and baricitinib + MTX groups suggest that baricitinib may be an effective monotherapy treatment.
These results from the current analysis are similar to what has been reported from studies of bDMARDs plus MTX in patients with early RA. For example, the PREMIER trial compared MTX monotherapy, adalimumab monotherapy, and adalimumab + MTX in patients with early RA who were naive to MTX therapy [
10]. For MTX, adalimumab, and adalimumab + MTX, respectively, the baseline HAQ-DI values were 1.5, 1.6, and 1.5 with decrements of − 0.8, − 0.8 and − 1.1 at 1 year [
10]. In the current RA-BEGIN analysis, at baseline, the mean baseline HAQ-DI scores for MTX, baricitinib monotherapy, and baricitinib + MTX, respectively, were 1.7, 1.6, and 1.6 with decrements of − 0.71, − 0.99 and − 1.06 at one year. Similar trends were also observed in the ORAL Start trial, which compared tofacitinib monotherapy, both 5 and 10 mg twice daily, to MTX monotherapy in MTX-naïve patients. On physical functioning, tofacitinib 5 mg and 10 mg demonstrated benefit compared to MTX as monotherapy [
11].
In RA-BEGIN, trends in the PRO results were also generally similar to PRO results from other studies. The HAQ-DI results in the OPTIMA trial were similar to the HAQ-DI observations described above [
34]. In the OPTIMA trial, which compared adalimumab + MTX with MTX monotherapy in patients with RA who were naïve to MTX therapy, the baseline mean HAQ-DI values were 1.61 for adalimumab + MTX and 1.60 for MTX. At week 26, the mean HAQ-DI values were 0.7 for adalimumab + MTX and 0.9 for MTX (p < 0.001) [
34].
Similar trends were observed with the FACIT-F, which measures fatigue, a major concern for patients and an important outcome measure in RA studies [
35]. Notably, as with most other PROs, it is not captured in the ACR response criteria or Disease Activity Score (DAS) response composite indices. The FACIT-F was assessed in the ORAL Start trial. At 6 months, the least-squares mean (LSM) changes from baseline for MTX, tofacitinib 5 mg, and tofacitinib 10 mg, respectively, were 6.3, 8.7, and 9.1 [
11,
36]. In the current analysis, the LSM changes from baseline to 6 months for MTX, baricitinib monotherapy, and baricitinib + MTX were 8.9, 13.3, and 12.2.
For the HRQOL assessments, patients in both baricitinib treatment groups reported statistically significant improvements in the EQ-5D index scores and VAS scores and the SF-36 PCS measure compared with MTX monotherapy at 4 weeks post baseline. These results were maintained through week 52. For the SF-36 MCS measure there was no statistically significant difference in the percentage of patients who met or exceeded the MCID (≥ 5) across the treatment groups. These SF-36 MCS results are consistent with previous observations from other clinical trials [
19,
20]. Of note, the baseline values for the SF-36 MCS ranged from 45 to 47 in the current analysis, which demonstrates a modest, rather than severe impairment. Patients, therefore, may have had less opportunity to improve their SF-36 MCS scores.
Work productivity and activity impairment have a significant economic impact on patients. In this trial, all three treatments were effective in improving work impairment, with earlier benefit noted in both baricitinib groups, but with comparable benefits at one year.
This study has a number of limitations. In clinical practice, in contradistinction to this study, MTX will typically be started either as monotherapy or in combination with other csDMARDs prior to the use of a bDMARD or a tsDMARD, such as baricitinib. However, the intent of this study was to compare the effectiveness of baricitinib to MTX and given current treatment paradigms, this is best accomplished in MTX-naïve patients. Following initial escalation, the maintenance dose of MTX was limited to no more than 20 mg/week; it is conceivable that there could have been a better response with MTX if the dose could have been increased or switched to subcutaneous MTX. In addition, other initial treatment regimens, such as MTX in combination with other csDMARDs, were not evaluated. Additionally, the use of carrying forward the last observations before rescue or discontinuation assumes that the PRO values would not change over time had these events not occurred. This is an appropriate statistical method for this analysis, but the assumption is not verifiable. Last, as in most double-blind comparator trials, the inclusion and exclusion criteria limited the participation of some patients, who are routinely seen in clinical practice. This may potentially impact the generalizability of the study results.
Competing interests
Financial Support and Disclosures: MS has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Johnson & Johnson, Novartis, Roche, and UCB (< US$10,000 each) and speaking fees from AbbVie and Bristol-Myers Squibb (> US$10,000). TT has received consulting fees from Pfizer Japan Inc., Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Daiichi Sankyo Co., Ltd., Nipponkayaku Co., Ltd, Janssen Pharmaceutical K.K., Merck Serono Co., Ltd., Takeda Pharmaceutical Co., Ltd. (< US$10,000 each), and from Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc, AbbVie GK, Bristol–Myers K.K. Asahi Kasei Medical K.K (> US$10,000 each), and speaking fees from Celtrion, Nipponkayaku Co., Ltd, Pfizer Japan Inc., UCB Japan, Diaichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., (< US$10,000 each) and from Chugai Pharmaceutical Co,. Ltd., AbbVie GK., Bristol–Myers K.K., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Janssen Pharmaceutical K.K., and Astellas Pharma Inc., (> US$10,000 each). RF has received consulting fees from AbbVie, Amgen, Bristol–Myers Squibb, Janssen, Eli Lilly and Company, and Sanofi-Aventis (< US$10,000 each), and consulting fees from Pfizer and UCB (> US$10,000 each). CG, AD, DS, W-LK, J-EW, TC, and TR are employees of Eli Lilly and Company and all, except TC and AD are shareholders. PD has received consulting fees from Eli Lilly and Company. SS has received consulting fees from Abbvie, Eli Lilly, Roche, and UCB. RPH has no conflicts of interest related to this manuscript. RvV has received consulting fees from AbbVie, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex and research grants from AbbVie, Amgen, BMS, GSK, Pfizer, Roche, and UCB. CAFZ has received consulting fees from Merck, Pfizer, Sanofi, and Eli Lilly and Company (< US$10,000 each).