Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: a matching-adjusted indirect comparison

INTRODUCTION

Despite substantial improvements over the last two decades in the management of patients with rheumatoid arthritis (RA), the treat-to-target approach has led rheumatologists to focus on inflammatory disease activity, whereas patients generally consider the reduction of pain and fatigue and improvement of physical function to be more important.^1–3 Their assessment, in addition to healthcare provider (HCP)-reported disease activity measures, should help physicians determine the best treatment management for the patient. In the RA-BEAM randomised controlled trial (RCT), with concomitant methotrexate (MTX), baricitinib 4 mg one time per day demonstrated greater improvements in pain and physical function compared with adalimumab 40 mg every other week in a population of patients who had had an insufficient response to MTX.⁴ There is an absence, however, of prospective, head-to-head trials between different biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in MTX-naïve RA patients, a population that could be considered more sensitive to change in PROs because they had not yet experienced the irreversible consequences of the longstanding disease.

In the absence of data from RCT, indirect comparison methodologies, such as Network Meta-Analysis (NMA) and, in more recent years, Matching-Adjusted Indirect Comparison (MAIC), have been proposed to compare the efficacy of different therapies based on aggregate data from different RCTs, and they are commonly used for the purposes of health technology appraisal.^5–7 Compared with an NMA, which is based on the assumption that treatment effects (TEs) are only relative to a common comparator (eg, placebo) with no additional difference between the trials in the distribution of effect-modifying variables,^{7 8} MAIC builds upon the indirect comparison through additional adjustment of effect-modifying variables.

An MAIC analysis uses patient-level data of a drug to match with published data from comparators. Specifically, individual patient data from one or more studies for one treatment are reweighted to match with the baseline characteristics, which are known to be TE modifiers, from a published study of another treatment. To have an appropriate analysis, the study with patient-level data and the study with published data must have a common reference arm for matching. After the matching with the individual patient data, the weighted difference in mean values of an outcome measure between the active arm and the reference arm of one study is calculated and compared with the difference from the other published study.⁵

The objective of this analysis was to compare improvement in pain and physical function between baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy with an MAIC using data from randomised, MTX-controlled trials in conventional synthetic DMARD (csDMARD)/bDMARD-naïve RA patients.

METHODS

Study eligibility

The studies included in this analysis were derived from a prior systematic literature review (SLR) that was designed for a NMA conducted by Eli Lilly. The SLR synthesised the evidence of treatments on measures of treatment response and effectiveness, disease activity, physical function, radiographic outcomes, safety and other key measures for adult patients with moderate-to-severe RA among studies conducted from 1999 to 2016. The criteria for selection in the SLR and a flow chart describing the screening for inclusion are in online supplementary figure 1. For the purposes of the current analysis, we focused on the population of patients with limited or no treatment with csDMARDs in the SLR; 27 studies met this criterion. Of these studies, 12 included monotherapy and an MTX treatment arm, which constitutes the common comparator; and of these 12 studies, 5 reported on pain and physical function, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI), at 6 months or 24±2 weeks, depending upon the time points reported in the studies. These five studies were included in the current analysis (table 1). The study designs and inclusion and exclusion criteria for the studies have been previously reported.^6–11 The doses of the medications included in the analysis were oral 4 mg of baricitinib daily,⁹ subcutaneous 40 mg of adalimumab every other week,^{6 7} intravenous 8 mg/kg of tocilizumab every 4 weeks^{8 10} and oral 5 mg tofacitinib two times per day.¹¹

Table 1

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Study design and characteristics

Figure 1

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Treatment differences from indirect comparisons with matching by treatment arm (primary analysis), matching by study and without matching. HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; VAS, visual analogue scale.

RESULTS

Sensitivity analyses

To confirm the robustness of these results, we conducted sensitivity analyses in which disease duration was an additional matching variable, and when data from AMBITION and FUNCTION were analysed together. These sensitivity analyses were generally consistent with the direction and magnitude of the primary results, except for the comparison with the AMBITION data (figures 2a,b). The different patient characteristics from AMBITION from those in the FUNCTION and RA-BEGIN studies may have contributed to the differences, as described in the discussion below.

Figure 2

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Sensitivity analyses with (a) disease duration included in the model and (b) with data from AMBITION and FUNCTION analysed separately. HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; VAS, visual analogue scale.

DISCUSSION

The gold standard for assessing the relative effectiveness of one medication compared with another is a properly powered head-to-head study using an appropriate metric as the primary endpoint. There has not been a study conducted comparing one JAK inhibitor with another, or with a bDMARD, in MTX-naïve patients, as monotherapy. In the absence of a head-to-head RCT, we applied an MAIC to compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, MTX-controlled trials in RA patients who were naïve to csDMARDs and bDMARDs. The MAIC enables greater flexibility to adjust for patient characteristics and TE modifiers and should provide a more robust indirect comparison than other traditional indirect comparison methods, such as a network meta-analysis.¹⁸ This MAIC analysis has been used in the indirect comparison of efficacy in other rheumatic diseases, such as psoriatic arthritis.^{19 20} The results of the current analysis suggest greater pain reduction with improved physical function for baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy with the primary MAIC and sensitivity analyses. For comparisons between baricitinib and tofacitinib monotherapy, greater pain reduction with baricitinib was not consistently observed across the MAIC analyses, which did not allow for a robust conclusion on a difference between the two molecules. There were no differences observed between the two JAK inhibitors for HAQ-DI. Similar observations were also observed with models in which disease duration was an additional matching variable and with models in which the AMBITION and FUNCTION data were analysed together.

To our knowledge, this is the first systematic analysis that compares patients receiving different csDMARD and bDMARD monotherapies in MTX-naïve patients with RA. This analytic approach offers many advantages over other conventional pairwise meta-analyses.²¹ Of note, the inclusion of active comparators provides more clinically relevant information compared with meta-analyses with only placebo. We also included data from well-designed RCTs that included large enough sample sizes to allow for more reliable estimations of differences between treatments.

There are, however, limitations intrinsic to the MAIC approach and, for this reason, our results should be interpreted with caution. The MAIC analysis matches based on observed TE modifiers, but it is not possible to control for variables that are unobserved. Additionally, the application of the MAIC reduces the effective sample size for the study with patient-level data, RA-BEGIN in the current analysis, which subsequently results in reduced power and capability to detect differences between medications. Importantly, the RCTs in the current analysis were conducted at different time periods during which more aggressive therapy was being introduced, with different patients and investigators in different regions of the world. These factors have the potential to increase the variations in baseline characteristics among the included studies, with consequent challenges in matching patients accurately. Of note, the AMBITION trial included 33% of patients who had been previously treated with MTX, but who had stopped MTX >6 months. Patients from AMBITION had a longer duration of disease, higher tender and swollen joint counts and higher CRP levels than the other studies included in this MAIC analysis; whereas, patients from FUNCTION tended to show more similar characteristics to those in RA-BEGIN; the other studies included patients who were naïve to treatment. Because of this, we included the AMBITION trial only as a sensitivity analysis. Also, parameters, such as race and geographic location, were not included in the analysis, because these parameters were not widely reported in the original trial publications. Additionally, these variables and the inclusion of geographic location have rarely been explored in indirect comparisons. Lastly, the baricitinib RCT in the MAIC was conducted before the drug and dosage for baricitinib received regulatory approvals; a monotherapy study with a 2 mg dose of baricitinib was not conducted.

In conclusion, this MAIC suggests that among RA patients who are naïve to csDMARDs and bDMARDs, baricitinib 4 mg provides statistically significant greater pain reduction and improvement of physical function compared with adalimumab 40 mg and tocilizumab 8 mg/kg. No difference in pain reduction was observed between baricitinib and two times per day tofacitinib 5 mg with two of the three analyses employed, and no difference was observed in improving physical function. Well-designed, properly powered, head-to-head clinical trials are needed to confirm whether there is a class effect for JAK inhibitors over bDMARDs.