Effectiveness and safety of initiating adalimumab plus ≥12 mg/week methotrexate with adjustable dosing in biologic-naïve patients with early rheumatoid arthritis: HAWK study postmarketing surveillance in Japan

Abstract

Objectives: This real-world study assessed the effectiveness and safety outcomes of initiating adalimumab and methotrexate (≥12 mg/week) with adjustable dosing in Japanese patients with early rheumatoid arthritis (RA).

Methods: This single-arm, prospective postmarketing observational study (conducted from September 2012 to March 2017 at 119 sites) enrolled biologic-naïve patients with early RA (≤2 years duration) and a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) >3.2 who were treated with methotrexate for ≥3 months and had initiated treatment with adalimumab and methotrexate (≥12 mg/week). This report presents 52-week data. The primary outcome was the proportion of patients who achieved DAS28-CRP scores <2.6 at week 52.

Results: Overall, 293 of 346 enrolled patients were included in the effectiveness population: women, 73%; mean (standard deviation) age, 54.3 (13.9) years; DAS28-CRP score, 4.51 (0.90); and modified total Sharp score (mTSS), 7.69 (9.98). At week 52, 77% of patients achieved clinical remission (DAS28-CRP <2.6), 92.3% achieved low disease activity (DAS28-CRP ≤3.2), and 86% of evaluable patients experienced structural remission (ΔmTSS ≤0.5).

Conclusion: Adalimumab plus methotrexate (≥12 mg/week) with adjustable dosing was well tolerated, and could be a beneficial treatment option for Japanese patients with early RA.

KEYWORDS:

• Adalimumab
• effectiveness
• methotrexate
• postmarketing surveillance
• rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that affects 0.5–1.0% of the global population [1]. According to the results of a study using reimbursement data from 2005 to 2011, nearly 1% of people between the age of 16 and 75 years (1.24 million) in Japan have RA [2]. Patients with uncontrolled RA suffer from progressive joint destruction, which leads to major disabilities and severely limits quality of life and social activities [3]. Methotrexate (MTX) is the standard of care as first-line monotherapy in treatment-naïve patients with RA and in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic disease-modifying antirheumatic drugs (DMARDs) in patients with an insufficient response to MTX [4–6]. Therefore, optimizing MTX therapy, especially determining appropriate initial and target dosages, is critical for the effective therapeutic management of patients with RA [7–9].

In Western countries, oral MTX is recommended at a starting dose of 10–15 mg/week, with dose escalation of 5 mg every 2–4 weeks, up to 20–30 mg/week [10]. However, until recently, the maximum MTX dose approved by Ministry of Health, Labor and Welfare (MHLW) in Japan was 8 mg/week [11]. In 2011, the MHLW approved a maximum oral dose of 16 mg/week as first-line therapy in adult patients with RA [12]. In addition to csDMARDs, the European League Against Rheumatism (EULAR) recommends treatment of patients with RA with an additional first-line biologic agent such as tumor necrosis factor-alpha (TNF-α) inhibitors, B- or T-cell inhibitors, interleukin-1 or interleukin-6 inhibitors, and Janus kinase inhibitors, preferably in combination with MTX or other csDMARDs [6].

Adalimumab (ADA; Humira^®, AbbVie Inc., North Chicago, IL, USA), a humanized anti–TNF-α monoclonal antibody, binds to TNF-α and blocks its interaction with cell surface TNF receptors and thus suppresses the biologic activity of this pro-inflammatory cytokine [13]. In 2008, ADA was approved in Japan for the treatment of RA in patients with inadequate response to conventional therapy. As a condition of the approval, an all-case survey of ADA was conducted in 7,740 Japanese patients with RA who received ADA between June 2008 and October 2010 [14,15]. The results suggested that ADA was more effective in biologic-naïve patients and in patients receiving ADA in combination with MTX in dosages of 10 mg/week [14,15]. Based on encouraging results from the phase III HOPEFUL-1 study [16] in which treatment-naïve patients with early RA and high disease activity achieved treatment success with ADA plus low-dose MTX (≤8 mg/week), the Japanese MHLW approved an additional indication for ADA: the prevention of structural joint damage in patients with RA. This approval in 2012 offered DMARD-naïve patients at risk of early structural joint damage an opportunity to receive ADA as a first-line RA therapy.

Early and aggressive treatment of RA is now considered the key to achieving sustained remission and consequently, improved structural and functional outcomes. However, data on the effectiveness and safety outcomes of initiating ADA in combination with higher-dose MTX (≥12 mg/week) are limited in Japan. The HAWK postmarketing observational study (PMOS) was conducted to assess the long-term clinical effectiveness (including inhibition of structural progression) and safety outcomes of initiating ADA plus higher-dose MTX (≥12 mg/week) in biologic-naïve patients with early RA in Japan. Herein, we present 52-week analysis of the HAWK study.

Materials and methods

Study design

For this ongoing, single-arm, multicenter, prospective PMOS, patients with RA were recruited from September 2012 to December 2014 from 119 sites in Japan. This study is registered at ClinicalTrials.gov (identifier: NCT01736189; retrospectively registered 27 November 2012). The observation period of the study was 104 weeks. In this report, interim 52-week data are presented, including last patient observations before the data cut-off. Discontinuation was defined as withdrawal from ADA treatment within 52 weeks from the start of the treatment or administration of biologics other than ADA after 52 weeks.

Ethics approval and consent to participate:

This study was a multi-institutional, prospective, non-interventional observational study that conformed to Good Post-marketing Study Practices (GPSP) according to MHLW ordinances. The study protocol was reviewed and approved in advance by the Pharmaceuticals and Medical Devices Agency of Japan. For this reason, no ethical review by the individual facilities participating in the study was required for this PMOS. Because informed consent is not required for PMOSs that are conducted under the GPSP in Japan, the present study did not solicit informed consent from the patients.

Patient cohort

Biologic-naïve Japanese patients with early RA (≤2 years disease duration) with a Disease Activity Score based on 28-joint count using C-reactive protein (DAS28-CRP) >3.2 who had been treated with MTX for ≥3 months and had initiated treatment with a combination of ADA and MTX (≥12 mg/week) were eligible for study inclusion.

Treatment

Eligible patients initiated treatment with combination ADA and MTX (≥12 mg/week) and were followed for 104 weeks or until early discontinuation of ADA. ADA was prescribed by the treating physician in accordance with the approved label for use in patients with RA. Physician discretion based on real-world treatment patterns was the basis for MTX dose adjustments and tapering in this study.

Effectiveness assessment

Data were collected from rheumatologists and orthopedic physicians in Japan who routinely treat patients with RA. Demographics and baseline patient characteristics were recorded. Comorbidities, concomitant therapies, ADA therapy status, RA therapies, and scores from disease activity measures such as DAS28-CRP, Disease Activity Score based on 28-joint count using erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Health Assessment Questionnaire-Disability Index (HAQ-DI) were to be measured at baseline and at weeks 12, 24, 52, 76, and 104. Radiographic progression, assessed as modified total Sharp score (mTSS), was to be recorded at baseline, week 52, and week 104. Interpretation of radiographic images was performed by independent third-party physicians.

For this 52-week analysis, the primary endpoint was to assess the proportion of patients who achieved clinical remission (DAS28-CRP <2.6) at week 52. Secondary endpoints included the evaluation of DAS28-ESR, CDAI, SDAI, and HAQ-DI scores, as well as measures of structural progression of RA using mTSS.

Safety

All adverse events (AEs) were recorded from the time of ADA initiation to ADA discontinuation. For this analysis, safety data reported from physicians through 15 April 2016, were analyzed. Physicians assessed the possibility of causality between ADA and any reported AEs using the most recent package insert for ADA and any concomitant drugs (e.g., MTX, corticosteroids). Adverse drug reactions (ADRs) were classified using the Medical Dictionary for Regulatory Activities, version 18.0, by system organ class designation. Safety was assessed by summarizing ADRs and serious ADRs.

Statistical analyses

Sample size calculation

As per the study conducted by Takeuchi et al. [17], the percentage of patients with a DAS28-CRP <2.6 at week 52 was 42.7% among those receiving MTX at a dose of 8.5 ± 2.9 mg/week and 61.7% among those receiving MTX at a dose of ≥12 mg/week. Assuming that 55% of patients receiving MTX at ≥12 mg/week at the initiation of ADA treatment will achieve a DAS28-CRP <2.6 at week 52 (estimated difference 12.3%), the number of patients required to achieve a power (1-β) of 0.90 at an α level of 0.05 (two-tailed) was 171 (one-sample test). As 32% of patients with RA who were enrolled in the all-case survey of ADA dropped out during the 24-week survey period, and assuming that 50% of participants would drop out during the 52-week survey period, a target enrollment sample size of 342 patients was determined.

Statistical methods

Our general biometric approach consisted of evaluating changes with descriptive statistical methods, as well as regression analysis of parameters influencing clinical effectiveness and additional stratified group analyses. The safety population included all patients who met safety analysis inclusion criteria (i.e., those who did not have violations of inclusion criteria or prior administration of study drug), and the effectiveness population comprised all patients from the safety population who had evaluable pretreatment and post-treatment DAS28-CRP assessments.

In this analysis, DAS28-CRP, DAS28-ESR, CDAI, SDAI, and HAQ-DI scores at weeks 0, 12, 24, and 52 and mTSS at week 52 were compared with baseline scores. Cut-off values of disease activity (high/medium/low) were defined for DAS28-CRP and DAS28-ESR (for both 5.1/3.2/2.6), SDAI (26/11/3.3), and CDAI (22/10/2.8) scores. Functional remission was defined as HAQ-DI ≤0.5. Structural remission was defined as ΔmTSS ≤0.5 at 52 weeks (ΔmTSS ≤0.5 per year). Additionally, the strength of the relationship between the predictors and the parameters of clinical effectiveness was determined. The impact of variables on therapeutic success was determined by regression analyses and illustrated by stratified group analyses. Inferential statistics were performed at a nominal level of significance (0.05; two-sided). The last observation denotes each patient’s result at his/her last observation time by the end of 52 weeks, including patients who discontinued earlier. Patients who did not achieve a response to ADA treatment discontinued the study; therefore, the observed efficacy at the last observation for these patients would be lower than at the 52-week time point.

Results

Patient demographics and baseline characteristics

A total of 346 patients were enrolled in the study. The safety and effectiveness populations comprised 301 and 293 patients, respectively (Figure 1). Of the 293 patients in the effectiveness population, the majority (214 [73.0%]) were women. The mean ± standard deviation (SD) age was 54.3 ± 13.9 years and the mean ± SD body weight was 57.1 ± 12.0 kg. Most patients (257 [87.7%]) had an RA disease duration of 6–24 months; the mean ± SD disease duration of patients was 12.1 ± 6.2 months. Patients were mainly classified into Steinbrocker stage [18] I or II (272 [92.8%]) and class I or II (266 [90.8%]). Mean ± SD disease activity scores were: DAS28-CRP, 4.51 ± 0.90; DAS28-ESR, 5.13 ± 1.04; SDAI, 25.0 ± 10.4; CDAI, 23.4 ± 9.9; HAQ-DI, 0.77 ± 0.64; and mTSS, 7.69 ± 9.98 (Table 1). The mean ± SD MTX dosage was 13.4 ± 1.8 mg/week at baseline. Approximately one-third of patients (103 [35.2%]) received concomitant treatment with corticosteroids.

Figure 1. Patient flow chart. ADA: adalimumab; DAS28-CRP: Disease Activity Score based on 28-joint count using C-reactive protein; I/E: inclusion/exclusion. *1 patient had violation of I/E criteria in whom ADA was administered before enrollment.

Table 1. Baseline characteristics and demographics of patients (effectiveness population, n = 293).

Baseline characteristics and demographics
Sex
Female, n (%)	214 (73.0)
Age (years)
n	293
Mean (SD)	54.3 (13.9)
Median (Min–Max)	56.0 (16–79)
Weight (kg)
n	265
Mean (SD)	57.1 (12.0)
Median (Min–Max)	55.0 (36.5–113.0)
RA duration (months)
n	293
Mean (SD)	12.1 (6.2)
Median (Min–Max)	12.0 (3.0–24.0)
Comorbidities, n (%)
Hepatic	28 (9.6)
Renal	3 (1.0)
Cardiovascular	38 (13.0)
Hematologic	10 (3.4)
Respiratory	13 (4.4)
Others	107 (36.5)
History of smoking, n (%)
No	189 (64.5)
Yes	68 (23.2)
Unknown	36 (12.3)
Steinbrocker stage, n (%)
Stage I	160 (54.6)
Stage II	112 (38.2)
Stage III	17 (5.8)
Stage IV	4 (1.4)
Steinbrocker class, n (%)
Class I	84 (28.7)
Class II	182 (62.1)
Class III	26 (8.9)
Class IV	1 (0.3)
Baseline MTX dose (mg/week)
Range, n (%)
12.0 to <14.0	168 (57.3)
14.0 to <16.0	44 (15.0)
≥16.0	81 (27.6)
n	293
Mean (SD)	13.4 (1.8)
Median (Min–Max)	12.0 (12–16)
Average MTX dose during treatment (mg/week)
n	293
Mean (SD)	12.7 (2.2)
Median (Min–Max)	12.0 (6–16)
Corticosteroid use
No	190 (64.8)
Yes	103 (35.2)
DAS28-CRP
n	293
Mean (SD)	4.51 (0.90)
Median (Min–Max)	4.37 (3.21–7.30)
DAS28-ESR
n	274
Mean (SD)	5.13 (1.04)
Median (Min–Max)	5.06 (2.58–7.93)
SDAI
n	290
Mean (SD)	25.0 (10.4)
Median (Min–Max)	22.6 (9.56–62.0)
CDAI
n	290
Mean (SD)	23.4 (9.9)
Median (Min–Max)	21.0 (6.2–53.2)
HAQ-DI
n	266
Mean (SD)	0.77 (0.64)
Median (Min–Max)	0.63 (0.00–2.50)
mTSS
n	199
Mean (SD)	7.69 (9.98)
Median (Min–Max)	4.00 (0.0–60.5)

CDAI: Clinical Disease Activity Index; DAS28-CRP: Disease Activity Score based on 28 joints using C-reactive protein; DAS28-ESR: Disease Activity Score based on 28 joints using erythrocyte sedimentation rate; HAQ-DI: Health Assessment Questionnaire-Disability Index; Min: minimum; Max: maximum; mTSS: modified total Sharp score; MTX: methotrexate; RA: rheumatoid arthritis; SD: standard deviation; SDAI: Simplified Disease Activity Index.

Clinical effectiveness of ADA plus ≥12 mg/week MTX with adjustable dosing

Disease activity based on DAS28-CRP and DAS28-ESR over 52 weeks

At week 52, clinical remission (DAS28-CRP <2.6) was observed in 77.0% of patients (161/209), and low disease activity (DAS28-CRP ≤3.2) was observed in 92.3% of patients (193/209) (Figure 2(A)). Similarly, when evaluated by DAS28-ESR, clinical remission (DAS28-ESR <2.6) was observed in 60.9% of patients (117/192), and low disease activity (DAS28-ESR ≤3.2) was observed in 81.8% of patients (157/192) at week 52 (Figure 2(B)). Significant changes in DAS28-CRP and DAS28-ESR from baseline were observed (paired t-test, p < 0.0001 for both). None of the stratifications of baseline demographic factors, except for baseline DAS28-CRP, contributed toward the odds of achieving clinical remission as assessed by univariate logistic regression analyses (Table S1).

Figure 2. Change in disease activity (DAS28-CRP and DAS28-ESR) over 52 weeks. (A) DAS28-CRP: Disease Activity Score based on 28-joint count using C-reactive protein; (B) DAS28-ESR: Disease Activity Score based on 28-joint count using erythrocyte sedimentation rate.

Following MTX dose adjustments, there were no significant differences in disease activity observed among patients who reduced MTX dosage by 2 mg/week, maintained MTX dosage, or increased MTX dosage over 52 weeks (Table S2). The proportion of patients receiving MTX in dosages ≥12 mg/week decreased over time; 90% of patients (n = 254) continued to receive MTX in dosages ≥12 mg/week at week 12; 82% (n = 209) at week 24; and 70% (n = 149) at week 52 (Figure S1). During the periods of week 0–12 and week 12–52, MTX dosage was reduced in a significantly higher proportion of patients who achieved a DAS28-CRP <2.6 at week 12 compared to those who did not (Figure S2).

Table 2. Safety (n = 301).

ADR	All		Serious
Total	80	26.6%	21	7.0%
ADRs by SOC
Infections and infestations	29	9.6%	9	3.0%
Investigations^a	16	5.3%	1	0.3%
Respiratory, thoracic, and mediastinal disorders	13	4.3%	3	1.0%
Hepatobiliary disorders	9	3.0%	0	0.0%
ADRs of particular interest
Tuberculosis	0	0.0%	0	0.0%
Pneumocystis jirovecii pneumonia	4	1.3%	4	1.3%
Pneumonia, bacterial^b	6	2.0%	4	1.3%
Herpes zoster	4	1.3%	0	0.0%
Malignancy^c	4	1.3%	4	1.3%
Interstitial lung disease	2	0.7%	2	0.7%
Sepsis	0	0.0%	0	0.0%
Pancytopenia	0	0.0%	0	0.0%
Reactivation of hepatitis B	0	0.0%	0	0.0%

ADR: adverse drug reaction; SOC: system organ class. ^aLiver function test abnormal (11), cholesterol increased (1), blood creatinine increased (1), blood pressure decreased (1), white blood cell count decreased (3), and alkaline phosphatase increased (1). The number shown in the brackets is the event number; thus, the total event number may exceed the total patient number. ^bPneumonia, pneumonia bacterial, pneumonia pneumococcal, pneumonia legionella, pneumonia streptococcal. ^cColon cancer, diffuse large B-cell lymphoma, ovarian cancer metastatic, and lung neoplasm malignant.

Disease activity based on CDAI, SDAI, and HAQ-DI scores

At week 52, 101 patients (49.3%), 105 patients (51.2%), and 141 patients (81.5%) achieved clinical remission based on CDAI, SDAI, and HAQ-DI scores, respectively (Figures 3(A–C)). Additionally, low disease activity at week 52 was reported in 83 patients (40.5%), 83 patients (40.5%), and 18 patients (10.4%) according to CDAI, SDAI, and HAQ-DI scores, respectively.

Figure 3. Disease activity: (A) CDAI, (B) SDAI, (C) HAQ-DI, and (D) mTSS rate at week 52. Disease activity assessed as CDAI, SDAI, and HAQ-DI over 52 weeks is shown in (A)–(C), respectively. CDAI: Clinical Disease Activity Index; HAQ-DI: Health Assessment Questionnaire-Disability Index; mTSS: modified total Sharp score; SDAI: Simplified Disease Activity Index.

Radiographic progression status based on change in mTSS

Of the 157 patients for whom joint X-rays were taken, 135 (86%) achieved structural remission (ΔmTSS ≤0.5) by week 52, and 118 (75.2%) achieved no radiographic progression (ΔmTSS ≤0.0). Four patients had rapid radiographic progression (ΔmTSS ≥5.0), indicating structural joint damage (Figure 3(D)). The mean MTX dosage in these patients was between 12.8 and 16.0 mg/week, and all four patients met DAS28-CRP eligibility criteria.

Of note, patients who did not achieve structural remission had significantly longer disease duration than those who achieved structural remission (14.6 ± 6.6 months vs. 10.8 ± 5.5 months, respectively; p = 0.004). In contrast, patients who achieved structural remission had baseline DAS28-CRP values similar to those who did not (4.51 ± 0.88 vs. 4.51 ± 0.96, respectively; p = 0.988).

Factors associated with structural remission

Results of univariate logistic regression analyses indicated that the likelihood of achieving structural remission was significantly higher in males (p = 0.036) and in patients in Steinbrocker stage I and II (p = 0.038), whereas the likelihood of structural remission was significantly lower in patients with a longer duration of disease (p = 0.005), a higher mTSS at baseline (p = 0.001), and no history of smoking (p = 0.044; Table S3). Since a substantial correlation was observed between the parameters of male sex and no history of smoking (−0.595), history of smoking was excluded from the multivariate logistic regression model. Results of multivariate logistic regression analyses showed that the likelihood of achieving structural remission was significantly higher in males (p = 0.033) and lower in patients with a higher mTSS score at baseline (p = 0.009; Table S4).

Safety

Among the 301 patients in the safety population, 93 (30.9%) discontinued ADA; 15 patients (16.1%) discontinued because of AEs (Figure S3, Table S5). ADRs were reported in 80 patients (26.6%), and serious ADRs occurred in 21 patients (7.0%; Table 2). These included infections and infestations (n = 9), respiratory, thoracic, and mediastinal disorders (n = 3), and investigation-related events (n = 1). ADRs of particular interest included Pneumocystis jirovecii pneumonia (n = 4), bacterial pneumonia (n = 4), malignancy (n = 4), and interstitial lung disease (n = 2). No deaths were reported.

Discussion

The results of this PMOS conducted in Japan showed high clinical and structural remission rates in biologic-naïve patients with early RA who initiated treatment with ADA and higher-dose MTX (≥12 mg/week) with adjustable dosing. At week 52, 77% of patients achieved clinical remission (DAS28-CRP <2.6) and 92% achieved low disease activity (DAS28-CRP ≤3.2). As some of the participating facilities could not measure ESR, the number of cases was insufficient to analyze clinical remission using DAS28-ESR and therefore, DAS28-CRP was primarily used for effectiveness evaluation in this study. When evaluating these parameters using DAS28-ESR, 60.9% of patients achieved clinical remission and 81.8% achieved low disease activity (DAS28-ESR <2.6 and ≤3.2, respectively) at week 52. The difference in clinical remission rates by DAS28-ESR and DAS28-CRP could be attributed to the similar cut-off values used for remission and low/moderate/high disease activity (2.6/3.2/5.1) in this study, which are also used globally. In an analysis using data from a large observational study in Japanese patients with RA, DAS28-ESR and DAS28-CRP showed a strong linear correlation. However, the threshold values of the two scores were inconsistent using receiver operating characteristic curve analysis with DAS28-CRP of 2.3, 2.7, and 4.1 corresponding to DAS28-ESR remission, low disease activity, and high disease activity, respectively [19]. Similarly, analysis of data from two global studies reported that a DAS28-CRP of 4.6 corresponds to a DAS28-ESR of 5.1, a discrepancy which could have affected our RA disease estimates [20]. Generally, patients achieved clinical remission regardless of baseline patient characteristics, MTX dose, or disease characteristics, with the exception of DAS28-CRP severity. This suggests that initiating ADA treatment in patients with lower disease activity may help to suppress disease activity. However, interpretations of efficacy results must take into account that patients who discontinued due to lack of efficacy were included in analysis.

Anti-TNF-α drugs are known to inhibit the progression of structural joint damage or quantifiable radiologic damage [21]. In the HOPEFUL-1 study, a significantly higher proportion of patients taking ADA plus MTX achieved structural remission (ΔmTSS ≤0.5) at 52 weeks compared with those taking placebo plus MTX (65.9% vs. 42.9%; p < 0.001) [12]. In our current study, structural remission (ΔmTSS ≤0.5) was achieved in 86% of patients with radiographic evaluation, a rate that was numerically higher than that of the HOPEFUL-1 study. These results must be interpreted with caution; the difference in clinical remission rates may be influenced by differences in study design and patient characteristics. Patients in HOPEFUL-1 were MTX-naïve and the average MTX dose was 6.2 mg/week in the ADA plus MTX group [16], compared with patients who had received MTX for ≥3 months in this PMOS. In addition, almost all patients in this PMOS continued concomitant MTX ≥12 mg/week for ≥6 months. Thus, the high rate of structural remission observed in the current study could be attributed to ADA in combination with the relatively higher dose of MTX (≥12 mg/week up to 16 mg/week) in biologic-naïve patients with early RA. While the optimum MTX dosage with TNF-α inhibitors has not been established, our real-world study showed that increasing MTX dosage to 12 mg/week or more and initiating treatment with ADA was a feasible and effective strategy for managing RA in Japanese patients.

Although a high number of patients achieved inhibition of radiographic progression in this study, four patients experienced rapid radiologic progression (ΔmTSS >5.0/year) despite improvement in disease activity. No comorbidities or baseline characteristics were common among these four patients; however, two patients whose ΔmTSS was >10/year were women with disease duration >20 months and baseline mTSS scores of 44 and 25. Multivariate logistic regression showed that male sex and lower mTSS score at baseline were statistically significant predictive factors for structural remission; however, these results were not consistent with those of HOPEFUL-1 [12] or ASPIRE [22], which involved MTX-naïve patients with early RA treated with escalating MTX doses (up to 20 mg/week), with or without infliximab. In HOPEFUL-1, baseline mTSS was not a significant predictor of radiographic progression at week 26, although lower CRP level was [16]. In ASPIRE, higher baseline mTSS score was a negative predictor of radiographic progression of joint damage for infliximab plus MTX treatment, largely because mTSS scores were decreased in some patients with higher mTSS scores at baseline [22]. In this study, male sex emerged as a positive predictor for structural remission although this was not observed in HOPEFUL-1 [16] and ASPIRE [22]. However, the reason for this discrepancy is not clear. In our study, radiographic progression >0.5 ΔmTSS was observed in only 22 patients. This small number of patients, along with other factors, might be the cause of the difference between our study results [23] and those of previous studies [12,22].

Tapering of MTX dosing

Optimization of ADA and MTX combination therapy necessitates the identification of the minimal effective dose of MTX [24]. In the CONCERTO trial, in which MTX- and biologic-naïve patients with early RA were treated with ADA and escalating doses of MTX to estimate the optimal starting dose of MTX when initiating combination therapy, efficacy significantly increased with each increase in MTX dose (however, the 10- and 20-mg/week dosages provided similar efficacy) [24]. Previous studies involving Japanese patients with RA receiving treatment with ADA in routine clinical practice settings also reported improved efficacy with concomitant use of higher dose MTX, with clinical remission rates of 57% (DAS28-ESR <2.6) at 24 weeks with MTX dose >8 mg/week [25] and 52.8% (DAS28 < 2.6) at 52 weeks with MTX dose ≥10 mg/week [26]. Additionally, these studies observed achievement of low disease activity by DAS28-ESR on trend analysis [25] and increased odds of achieving DAS remission on combination therapy with ADA and higher dose MTX [26].

According to EULAR treatment guidelines, it is important to sustain the treatment target. Although the term ‘sustain’ has not been precisely defined, ≥6 months have been suggested as a minimal time frame, requiring close follow-up and a strategy to adapt therapy [6]. In this regard, we did not find any significant differences in disease activity improvement among patients who underwent MTX dose reduction, maintained a dosage of 12 mg/week, or received >12 mg/week, indicating that physicians could manage MTX dose adjustment in their everyday clinical practices without compromising effectiveness. These findings are clinically relevant, as physicians in a real-world scenario may reduce the dosage of MTX in patients who achieve clinical targets to minimize the risk of AEs, even when high-dose MTX is generally well tolerated. This tendency was evident in our study; high-dose MTX was reduced in a significantly higher proportion of patients who achieved a DAS28-CRP <2.6 than those who did not within three months for the periods of 0–12 weeks and 12–52 weeks. Whether this strategy has long-term benefits has yet to be explored.

Safety

No new safety concerns were raised in this PMOS. Furthermore, the ADR profile of ADA was not affected by MTX dose adjustments. In this study, 93 patients (30.9%) discontinued ADA by week 52, with 15 patients (16.1%) discontinuing because of AEs. The rate of individual/observed AEs in the current study is lower than that of an all-case postmarketing surveillance of ADA involving 7740 patients (2250 [29.1%] discontinued early, 767 [9.9%] because of AEs) [14]. The difference among these two reports may be an outcome of the inherent dissimilarities in patient demographics and baseline characteristics. In our study, the proportion of patients at high risk for AEs, such as those associated with old age, impaired renal function, or pulmonary disease, was low because these patients could not tolerate/could not qualify for an MTX dosage of ≥12 mg/week. Further, baseline comorbidities varied between our study and the all-case postmarketing surveillance, with lower rates of cardiovascular (13.0% vs. 22.4%), respiratory (4.4% vs. 13.4%), hematologic (3.4% vs. 7.4%), and renal (1.0% vs. 3.3%) disorders, and a higher rate of hepatic disorders (9.6% vs. 5.8%) [14]. Overall, ADRs and serious ADRs were reported in 80 patients (26.6%) and 21 patients (6.9%), respectively; 29 patients (9.6%) had infections, and 9 patients (2.99%) had serious infections. These rates were similar to those in the all-case postmarketing surveillance [14].

Limitations of this study include the small number of patients (n = 157) who were evaluable for ΔmTSS, as X-ray images were taken during routine practice and not all patients underwent imaging at every time point. Another limitation was the lack of direct comparisons with randomized controlled trials due to this study’s observational study design. Conversely, a strength of this study is that it depicts a real-world clinical scenario.

In conclusion, this PMOS is the first to demonstrate the tolerability and effectiveness of ADA plus higher-dose MTX (≥12 mg/week) in biologic-naïve Japanese patients with early RA with an inadequate response to MTX. Combination therapy with ADA and high-dose MTX achieved high clinical and structural remission rates in patients with early RA, suggesting that initiation of ADA therapy in combination with relatively high-dose MTX in early RA could be an effective strategy to minimize the risk of progressive structural joint damage. Of note, the results of this study indicated that low disease activity could be maintained by tapering MTX doses in patients who have achieved clinical goals. Most importantly, no new concerns regarding the safety of ADA and MTX combination therapy were observed.

Conflict of interest

Yoshiya Tanaka has received speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, AbbVie, YL Biologics, Bristol-Myers Squibb, GlaxoSmithKline, UCB, Mitsubishi Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi Kasei and has received research grants from Mitsubishi Tanabe, Bristol-Myers Squibb, Eisai, Chugai, Takeda, AbbVie, Astellas, Daiichi Sankyo, Ono, MSD, and Taisho Toyama.

Hisashi Yamanaka has received research grants from AbbVie GK, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and UCB; has received consulting fees from AbbVie GK, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and UCB; and has received speakers bureau fees from AbbVie GK, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and UCB.

Tsuneyo Mimori has received grants and research supports from Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Nippon Kayaku, Mitsubishi Tanabe, Pfizer, and Sanofi, and has received speaker fees from Bristol-Myers Squibb, Chugai, and Mitsubishi Tanabe.

Ryo Nakajima, Kazuo Morita, and Junko Kimura are full-time employees of AbbVie GK.

Tsutomu Takeuchi has received research grants from Astellas, Chugai, Daiichi Sankyo, Takeda, AbbVie, Asahi Kasei, Mitsubishi Tanabe, Pfizer, Eisai, AYUMI, Nippon Kayaku, and Novartis; has received speaker fees from AbbVie, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe, Pfizer, Astellas, Daiichi Sankyo, Eisai, Sanofi, Teijin, Takeda, and Novartis; and has received consultant fees from AstraZeneca, Eli Lilly, Novartis, Mitsubishi Tanabe, AbbVie, Nippon Kayaku, Janssen, Astellas, Taiho, Chugai, Taisho Toyama, GlaxoSmithKline, and UCB.

Acknowledgements

The authors wish to thank Dr. Eiichi Tanaka, Dr. Shintaro Hirata, Dr. Yuko Kaneko, Dr. Hidekata Yasuoka, Dr. Tomohiro Koga, and Dr. Akitomo Okada for radiographic image interpretation. The authors also thank EPS Corporation for data analysis and Annirudha Chillar, MD, PhD, of Cactus Communications for editorial support, in the form of medical writing, assembling tables and creating high-resolution images based on the authors’ detailed directions, collating author comments, copyediting, fact checking, and referencing.

Additional information

Funding

This study (NCT01736189) was funded by AbbVie GK and Eisai Co., Ltd. AbbVie participated in the collection, analysis, and interpretation of the data, and in the drafting, review, and approval of the manuscript. AbbVie GK and Eisai Co., Ltd. provided funding to EPS Corporation for data analysis and to Cactus Communications for editorial assistance.