Effectiveness, safety, and methotrexate dose-tapering pattern over two years of treatment with adalimumab and ≥12 mg/week methotrexate for early rheumatoid arthritis: Results of the HAWK postmarketing surveillance study in Japan

Abstract

Objectives: To investigate the long-term effectiveness, safety, and methotrexate (MTX) dose-tapering patterns in patients with rheumatoid arthritis (RA) receiving adalimumab plus high-dose MTX.

Methods: In this prospective, postmarketing study (2012–2017), conducted at 128 sites in Japan, biologic-naïve patients with RA (duration ≤2 years) previously treated with MTX for ≥3 months, initiated treatment with adalimumab and MTX (≥12 mg/week). Effectiveness by Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP), safety, and MTX dose-tapering were assessed from baseline to 104 weeks.

Results: In the effectiveness analysis set (n = 292), DAS28-CRP remission (<2.6) was achieved in 92.3% (n = 120/130) of patients at week 104. The proportions of patients receiving MTX dose <10 mg/week increased to 32.3% (n = 50/155) and ≥12 mg/week reduced to 52.9% (n = 82/155) by week 104. Per univariate regression analysis, MTX dose tapering was associated with longer adalimumab drug survival. Of 70 patients with joint X-rays available, 59 (84.3%) achieved Δ modified total Sharp score ≤1.0 at 104 weeks. In the safety analysis set (n = 300), 143 adverse drug reactions were reported in 92 patients (30.7%, non-serious; 24.7%, serious 8.7%).

Conclusion: The long-term effectiveness and safety of adalimumab with high-dose MTX was confirmed in biologic-naïve patients with early RA in a real-world setting in Japan.

Clinical Trial Registration: This study is registered at ClinicalTrials.gov (identifier: NCT01736189; retrospectively registered 29 November 2012, due to administrative reasons).

Keywords:

• Adalimumab
• dose tapering
• methotrexate
• Japan
• postmarketing

Introduction

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting the synovial joints, with an estimated worldwide prevalence of 0.24% according to the global burden of disease 2010 study [1]. The prevalence of RA in Japan was estimated to be between 0.6% and 1.0% (0.706–1.24 million) from 2005 to 2011 [2].

Methotrexate (MTX) is the recommended first-line treatment for patients with RA [3–5]. MTX is recommended as the first-choice conventional synthetic disease-modifying antirheumatic drug (DMARD) for the management of patients with RA with poor prognosis, based on risk–benefit evaluations according to the Japan College of Rheumatology (JCR) [5]. Treatment with MTX was approved in Japan in 1999 at a weekly dose of 6–8 mg; in 2011, MTX was approved as a first-line drug for RA at a maximum weekly dose of 16 mg [5]. The JCR 2016 guidelines recommend initiating treatment with MTX at a dose of 6–8 mg/week and escalating the dose to a maximum of 16 mg/week in patients with RA with an inadequate response [5]. In patients who do not achieve treatment goals with an adequate MTX dose (usually ≥10–12 mg/week for 3–6 months), the JCR guidelines also recommend combination therapy with MTX (up to 16 mg/week), plus either another conventional synthetic DMARD or a biologic DMARD or a targeted synthetic DMARD based on a risk–benefit assessment [5]. However, the maximum MTX dose of 16 mg/week is specific to the license for Japan, and this dosage is lower than that approved in Western countries, where dose escalation to 20–30 mg/week is recommended [6].

Evidence from previous, randomized controlled trials has indicated that combination therapy with a biologic DMARD and MTX has a significantly greater impact on slowing radiographic disease progression in patients with early RA than MTX treatment alone [7]. A post hoc analysis of the OPTIMA study, including MTX-naïve patients with early RA (duration <1 year), found that initiating combination treatment with MTX and a tumor necrosis factor (TNF) inhibitor later in the disease course, rather than earlier, led to similar longer-term clinical outcomes but resulted in a small but significant amount of radiographic damage [8].

Adalimumab (HUMIRA^®, AbbVie Inc., North Chicago, IL), a humanized anti-TNF-α antibody, was approved in Japan in 2008 for the treatment of patients with RA with inadequate response to conventional therapy [9]. The results from an all-case survey indicated that adalimumab was more effective in biologic-naïve patients than those who had previously received biologics and when combined with MTX [10,11]. Adalimumab was additionally approved in Japan in 2012 for the prevention of structural joint damage in patients with RA [12] in combination with low-dose (≤8 mg/week) MTX, based on the results of the phase III HOPEFUL 1 study [13].

Previous studies have shown that concomitant high-dose MTX at baseline with biologics, including adalimumab and etanercept, has a significant effect on Disease Activity Score in 28 joints (DAS28) remission [14,15]. This regimen is also a predictor of good long-term clinical response in patients with RA receiving first-line biologics [15]. In the CONCERTO trial, a double-blind, parallel-arm study, patients with early RA treated with adalimumab in combination with MTX at a weekly dose of ≥10 mg achieved better results than patients treated with lower doses [16]. Significantly greater improvement in the proportion of patients achieving low disease activity (DAS28-C-reactive protein (CRP) <3.2) with combination therapy was achieved with increasing doses of MTX (2.5–20 mg/week) [16]. In MUSICA, another double-blind, parallel-arm study in patients with moderate to severe RA, patients with an inadequate response to MTX who were treated with adalimumab achieved greater improvements in Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) scores with concomitant MTX treatment at higher doses (20 mg/week) compared with lower doses (7.5 mg/week) [17].

Published reports of dosing patterns of concomitant MTX with TNF inhibitors are limited. However, it has been observed that in routine practice, MTX is often tapered or discontinued in patients receiving concomitant treatment with a TNF inhibitor [15,18], most frequently because of intolerance or adverse events (AEs) [15]. In the MELODY study, a post hoc analysis of an adalimumab all-case survey in Japan, it was observed that in biologic-naïve patients with established RA, there was a dose-dependent increase in the rates of low disease activity and remission up to an MTX dose of 8 mg/week [19]. However, no improvements in disease activity and remission rates were noted at doses higher than 8 mg/week, suggesting that concomitant MTX at doses up to 8 mg/week were sufficient in this patient population [19].

The HAWK study was conducted to investigate the long-term clinical effectiveness and safety outcomes of adalimumab plus MTX (≥12 mg/week) in biologic-naïve patients with early RA in a real-world setting in Japan. To ascertain the dosing patterns of concomitant MTX with adalimumab in patients with RA, additional post hoc analyses were conducted. The interim 52-week results from the HAWK study showed that adalimumab plus MTX (≥12 mg/week) with adjustable dosing was well tolerated, and low disease activity could be maintained by tapering MTX doses in patients who had achieved clinical goals [20]. Here, we present the 104-week results from the HAWK study.

Methods

Study design

This was a single-arm, multicenter, prospective postmarketing observational study (PMOS) conducted from September 2012 to March 2017 at 128 sites in Japan. Eligible patients were enrolled from September 2012 to December 2014 and were followed for 104 weeks or until study discontinuation. Biologic-naïve patients with early RA (duration ≤2 years) and DAS28-CRP scores >3.2, who were previously treated with MTX for ≥3 months, were included in the study. Detailed patient criteria are available in the interim analysis publication of this study [20].

The study protocol was reviewed and approved before study initiation by the Pharmaceuticals and Medical Devices Agency of Japan; therefore, no ethical review by the individual facilities participating in the study was required. This study conformed to Good Post-marketing Study Practice (GPSP) according to Ministry of Health, Labour and Welfare ordinances. Informed consent is not required from patients included in PMOSs conducted under GPSP in Japan.

Study assessments

Effectiveness assessments included: (i) disease activity (high/moderate/low) at baseline and at weeks 12, 24, 52, 76, and 104 as measured by DAS28-CRP (high/moderate/low cut-off values: 5.1/3.2/2.6, remission was defined as <2.6 [21]), DAS28-erythrocyte sedimentation rate (DAS28-ESR; high/moderate/low cut-off values: 5.1/3.2/2.6, remission was defined as DAS28-ESR <2.6 [21]), Clinical Disease Activity Index (CDAI) scores (high/moderate/low cut-off values: 22.0/10.0/2.8; remission was defined as CDAI ≤2.8) [21], and Simplified Disease Activity Index (SDAI) scores (high/moderate/low cut-off values: 26.0/11.0/3.3; remission was defined as SDAI ≤3.3) [21]); (ii) patient-reported functional impairment using Health Assessment Questionnaire-Disability Index (HAQ-DI) scores at baseline and weeks 12, 24, 52, 76, and 104 (high/moderate/low cut-off values: 1.5/1.0/0.5, functional remission was defined as HAQ-DI ≤0.5); (iii) patient-reported quality of life using EuroQol-5 Dimensions (EQ-5D) scores at baseline and weeks 12, 24, 52, 76, and 104; and (iv) radiographic progression using the modified total Sharp score (mTSS; ΔmTSS ≤0.5 per year: structural remission; ΔmTSS ≤0.0: no radiographic progression) at baseline and at weeks 52 and 104. The radiographic images were interpreted by independent third-party physicians.

Exploratory assessments included: (i) MTX dose tapering from baseline to weeks 12, 24, 52, 76, and 104 and (ii) DAS28-CRP and HAQ-DI scores at baseline and weeks 12, 24, 52, 76, and 104, as well as mTSS scores at baseline and at weeks 52 and 104 by MTX dose (<8 mg/week, ≥8 to <10 mg/week, ≥10 to <12 mg/week, and ≥12 mg/week). Safety assessments included the incidence of adverse drug reactions (ADRs) and serious ADRs overall and in patients who did and did not undergo tapering of MTX.

Statistical analysis

Study sample size calculation and statistical methods used in the study are described in detail in the 52-week interim analysis publication of the study [20]. The p values for change in effectiveness scores from baseline were calculated using a paired t test. Univariate logistic regression analyses were conducted for baseline factors impacting MTX dose tapering at the last observation and adalimumab discontinuation.

Results

Patient disposition

Of 346 enrolled patients, 300 were included in the safety analysis set and 292 were included in the effectiveness analysis set (Supplementary Appendix Figure 1). Overall, 46 patients were excluded from the safety analysis set because of protocol deviations and/or study drug administration before signing the contract with the participating hospital; a further eight patients were excluded from the effectiveness analysis set because DAS28-CRP scores could not be evaluated. Overall, 151 patients (50.3%) discontinued adalimumab (Supplementary Appendix Figure 2) over 104 weeks, with the most common reasons being inadequate efficacy (30.5%), improvement in symptoms/remission (19.9%), patient refusal (19.2%), no follow-up visit (15.9%), and AEs (15.2%). During the initial 24 weeks of the study, most patients discontinued due to inadequate efficacy and AEs (Supplementary Appendix Table 1). The proportion of patients who discontinued adalimumab because of improvement in symptoms or remission increased with treatment duration (up to 24 weeks, 4.3% [2/300]; up to 52 weeks, 21.4% [9/254]; and up to 104 weeks, 24.6% [14/211]; Supplementary Appendix Table 1).

Baseline patient demographics and characteristics

The safety analysis set comprised mostly female patients (73.7%). The mean (standard deviation (SD)) age was 54.1 (13.9) years and the mean (SD) RA duration was 12.2 (6.2) months for patients in the safety analysis set (Table 1). The mean (SD) MTX dose was 13.4 (1.7) mg/week and most patients (57.3%) were receiving MTX at a dose between 12.0 and 14.0 mg/week; 34.7% of patients previously received treatment with corticosteroids. The highest proportions of patients were classified as having Steinbrocker stage I (54.7%) and class II (63.0%).

Table 1. Baseline demographics and patient characteristics (safety and effectiveness analysis set).

Baseline characteristic^a	Safety analysis set (n = 300)	Effectiveness analysis set (n = 292)
Sex, female	221 (73.7)	214 (73.3)
Age (years)
Mean (SD)	54.1 (13.9)	54.2 (13.9)
Weight^b (kg)
Mean (SD)	57.0 (12.0)	57.1 (12.0)
RA duration (months)
Mean (SD)	12.2 (6.2)	12.1 (6.2)
Comorbidities
Hepatic	29 (9.7)	28 (9.6)
Renal	3 (1.0)	3 (1.0)
Cardiovascular	39 (13.0)	38 (13.0)
Hematologic	10 (3.3)	10 (3.4)
Respiratory	14 (4.7)	13 (4.5)
Others	111 (37.0)	108 (37.0)
History of smoking	69 (23.0)	68 (23.3)
MTX dose
Mean (SD)	13.4 (1.7)	13.4 (1.8)
≥12.0 to <14.0 mg/week	172 (57.3)	168 (57.3)
≥14.0 to <16.0 mg/week	46 (15.3)	44 (15.0)
≥16.0 mg/week	82 (27.3)	80 (27.4)
Previous corticosteroid use	104 (34.7)	102 (34.9)
Steinbrocker stage
Stage I	164 (54.7)	159 (54.5)
Stage II	114 (38.0)	112 (38.4)
Stage III	17 (5.7)	17 (4.8)
Stage IV	5 (1.7)	4 (1.4)
Steinbrocker class
Class I	84 (28.0)	83 (28.4)
Class II	189 (63.0)	182 (62.3)
Class III	26 (8.7)	26 (8.9)
Class IV	1 (0.3)	1 (0.3)

MTX: methotrexate; RA: rheumatoid arthritis; SD: standard deviation.

^a Data are n (%) unless indicated otherwise.

^b For weight, n = 272 in safety analysis set; n = 265 in effectiveness analysis set.

Effectiveness

Clinical remission as measured by DAS28-CRP and DAS28-ESR was observed as early as 12 weeks in 61.5% of patients (n = 168/273) and 42.9% of patients (n = 106/247), respectively, and was achieved in 92.3% of patients (n = 120/130) and 80.8% of patients (n= 97/120), respectively, at week 104 (Figure 1(a,b)). Early remission occurred at 12 weeks in 24.4% of patients (n = 66/270) and 27.1% of patients (n = 73/269) as measured by the CDAI and SDAI and the remission rate at week 104 was 69.5% (n = 91/131) and 73.4% (n = 94/128), respectively (Figure 1(c,d)). Similarly, functional remission as measured by HAQ-DI scores was achieved in 71.7% of patients (n = 167/233) at week 12 and 90.5% of patients (n = 95/105) at week 104 (Figure 1(e)). The mean (SD) EQ-5D score significantly improved from 0.6285 (0.1350) at baseline to 0.8888 (0.1631) at week 104 (Figure 1(f)). Similarly, significant improvements were observed in DAS28-CRP, DAS28-ESR, CDAI, SDAI, and HAQ-DI scores from baseline to 104 weeks (Supplementary Appendix Table 2). Of 70 patients with joint X-ray results available at 104 weeks, 59 (84.3%) achieved ΔmTSS ≤1.0, including 41 (58.6%) with no radiographic progression and 52 (74.3%) maintained ΔmTSS ≤0.5 (Figure 2).

Figure 1. Change in effectiveness measures over time. (a) DAS28-CRP. (b) DAS28-ESR. (c) CDAI. (d) SDAI. (e) HAQ-DI. (f) EQ-5D score. Data <1.0% are represented in the bars but are not labeled. CDAI: Clinical Disease Activity Index; DAS28-CRP: Disease Activity Score in 28 joints using C-reactive protein; DAS28-ESR: Disease Activity Score in 28 joints using erythrocyte sedimentation rate; EQ-5D: EuroQol-5 Dimensions; HAQ-DI: Health Assessment Questionnaire-Disability Index; SD: standard deviation; SDAI: Simplified Disease Activity Index.

Figure 2. Change in mTSS over time. mTSS: modified total Sharp score.

MTX dose tapering

The proportion of patients receiving an MTX dose ≥12 mg/week decreased over time (week 12, 88.8% [n = 253/285]; week 52, 69.7% [n = 154/221]; week 104, 52.9% [n = 82/155]; Figure 3). At week 104, concomitant MTX was tapered to <10 mg/week in 32.3% of patients (n = 50/155) and ≥10 to <12 mg/week in 14.8% of patients (n = 23/155; Figure 3).

Figure 3. Rate of MTX tapering over time. MTX: methotrexate.

Remission by MTX dose at week 104

Mean DAS28-CRP score of <2.6 was achieved in all MTX dose groups as early as 12 weeks and was sustained until 104 weeks (<8 mg/week, 1.31; ≥8 to <10 mg/week, 1.54; ≥10 to <12 mg/week, 1.62; ≥12 mg/week, 1.62). The improvements in DAS28-CRP scores from baseline were significant (p < .0001) at each time point in all MTX dose groups (Figure 4(a)); however, there was no significant difference between the dose groups at week 104 (p = .5385). Among patients who completed 104 weeks of treatment with adalimumab, 30% of patients (n = 39/130) achieved DAS28-CRP score of <2.6 with MTX doses <10 mg/week (Figure 4(a)).

Figure 4. Change in effectiveness scores by MTX dose over time. (a) DAS28-CRP. (b) HAQ-DI. (c) mTSS. DAS28-CRP: Disease Activity Score in 28 joints using C-reactive protein; HAQ-DI: Health Assessment Questionnaire-Disability Index; mTSS: modified total Sharp score; MTX: methotrexate; SD: standard deviation.

Similarly, patients in all MTX dose groups achieved mean HAQ-DI score of ≤0.5 as early as 12 weeks, and it was sustained until 104 weeks (Figure 4(b)). There was no significant difference in change from baseline between the dose groups at week 104 (p = .7665). The change in mTSS score in each MTX dose group over the study period is shown in Figure 4(c). Patients with baseline mTSS scores >20 and in whom mTSS scores worsened during the treatment period were also included in the MTX <8 mg and ≥12 mg dose groups at week 104. The differences in change from baseline to week 104 in mTSS scores were also not significant between the MTX dose groups (p = .6786).

Regression analysis

Per univariate logistic regression analysis, the baseline factors of RA duration, age, sex, Steinbrocker stage, concomitant DMARD (excluding MTX), and corticosteroid use did not impact MTX dose tapering at the last evaluation (Supplementary Appendix Table 3). However, another univariate regression analysis for adalimumab discontinuation showed that the odds ratio was significantly lower (odds ratio, 0.406; p = .0001) in the MTX-tapered group (Supplementary Appendix Table 4).

Safety

Overall, 143 ADRs were reported in 92 patients (30.7%), with a 24.7% and 8.7% incidence of non-serious and serious ADRs, respectively (Table 2). Non-serious ADRs were reported more frequently in patients who underwent MTX tapering (37.5%) compared with those who did not (14.0%) and most frequently in the system organ class (SOC) ‘investigations’ (12.5%) and ‘infections and infestations’ (7.3%) in the MTX-tapered and non-tapered groups, respectively (Table 2). In the MTX-tapered group, the second most frequently occurring ADRs were in the SOCs ‘infections and infestations’ and ‘hepatobiliary disorders,’ with an incidence of 8.8% each. The incidence of non-serious ADRs in all SOCs, except nervous system disorders, was higher in the MTX-tapered group compared with the non-tapered group.

Table 2. ADRs in patients with or without methotrexate dose tapering.

	Total N = 300		Methotrexate dose tapered n = 136		Methotrexate dose not tapered n = 164
	Non-serious ADRs	Serious ADRs	Non-serious ADRs	Serious ADRs	Non-serious ADRs	Serious ADRs
Overall, n (%)	74 (24.7)	26 (8.7)	51 (37.5)	13 (9.6)	23 (14.0)	13 (7.9)
Number of events	112	31	82	16	30	15
ADRs by SOC, n (%)
Infections and infestations	24 (8.0)	11 (3.7)	12 (8.8)	7 (5.2)	12 (7.3)	4 (2.4)
Investigations	19 (6.3)	1 (0.3)	17 (12.5)	0	2 (1.2)	1 (0.6)
Hepatobiliary disorders	12 (4.0)	0	12 (8.8)	0	0	0
Respiratory, thoracic, and mediastinal disorders	11 (3.7)	2 (0.7)	8 (5.9)	0	3 (1.8)	2 (1.2)
General disorders and administration site conditions	11 (3.7)	0	8 (5.9)	0	3 (1.8)	0
Gastrointestinal disorders	9 (3.0)	2 (0.7)	6 (4.4)	0	3 (1.8)	2 (1.2)
Skin and subcutaneous tissue disorders	9 (3.0)	1 (0.3)	5 (3.7)	1 (0.7)	4 (2.4)	0
Metabolism and nutrition disorders	2 (0.7)	0	2 (1.5)	0	0	0
Nervous system disorders	2 (0.7)	2 (0.7)	0	1 (0.7)	2 (1.2)	1 (0.6)
Musculoskeletal and connective tissue disorders	2 (0.7)	0	2 (1.5)	0	0	0
Renal and urinary disorders	1 (0.3)	3 (1.0)	1 (0.7)	2 (1.5)	0	1 (0.6)
Reproductive system and breast disorders	1 (0.3)	1 (0.3)	1 (0.7)	1 (0.7)	0	0
Neoplasms benign, malignant, and unspecified (including cysts and polyps)	0	4 (1.3)	0	2 (1.5)	0	2 (1.2)
Blood and lymphatic system disorders	0	2 (0.7)	0	1 (0.7)	0	1 (0.6)

ADR: adverse drug reaction; SOC: system organ class.

Discussion

In this real-world study in biologic-naïve patients with early RA who initiated treatment with adalimumab and MTX (≥12 mg/week) with adjustable dosing, remission occurred as early as 12 weeks. More than 90% of patients who continued adalimumab for 104 weeks achieved DAS28-CRP clinical remission and patient-reported functional remission.

Over the course of the study, the proportion of patients who discontinued adalimumab because of improved symptoms/remission increased with treatment duration, and improved symptoms led to discontinuation in almost one-fifth of patients up to 104 weeks. Early administration of adalimumab with MTX, followed by biologic-free maintenance, was also suggested as a potential treatment option in patients with early RA in a real-world setting in the HOPEFUL2 study [22].

During the interim analysis at 52 weeks in the HAWK study, the remission rates as measured by DAS28-CRP, DAS28-ESR, CDAI, SDAI, and HAQ-DI were 77.0%, 60.9%, 49.3%, 51.2%, and 81.5%, respectively [20]. Compared with the findings at 52 weeks [20], remission rates improved further at 104 weeks and consistent improvements were observed through 104 weeks of treatment in this study. Of those patients with joint X-ray results available, 84.3% (59/70) showed ΔmTSS ≤1.0 at week 104, possibly considered as ΔmTSS ≤0.5/year, and this was similar to the rate of structural remission at 52 weeks (86%) indicating that structural remission was potentially maintained with adalimumab treatment. However, the results cannot be directly compared because the number of patients with joint X-rays at the two time points was not the same [20]. Overall, ADRs and serious ADRs were reported in 24.7% and 8.7% of patients, respectively, in this study. These rates are comparable with those at 52 weeks (ADRs, 26.6%; serious ADRs, 7.0%) [20]. Thus, there were no increased safety concerns with an increase in the duration of combination treatment.

In the present study, the MTX dose was tapered in almost 50% of patients who continued adalimumab for 2 years, with the dose reduced to <10 mg/week in approximately one-third of patients overall, without any negative impact on the effectiveness or long-term continuation of adalimumab. This was also supported by the univariate regression analysis that showed greater odds of drug survival in patients who tapered MTX. Thus, these results could possibly indicate that the MTX dose was adjusted appropriately, according to disease activity, and that patients were monitored carefully in real-world clinical practice. This is consistent with results from the analysis of the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry, in which DAS28 scores in patients with RA who were first-time users of TNF inhibitors (infliximab, adalimumab, or etanercept) followed a similar course over time after initial improvement in both those patients who tapered/discontinued MTX and in those who continued MTX [18]. The DREAM registry also reported an approximately 25% reduced risk of discontinuing TNF inhibitors in patients who tapered their MTX dose (baseline MTX dose, <10 to >30 mg) [18]. However, univariate regression analysis results from the present study need further confirmation by multivariate analysis and therefore, may not be conclusive. Moreover, patients who taper MTX in an observational setting are more likely to be well-controlled, which could also impact drug survival rates.

In the current study, DAS28-CRP clinical remission (score <2.6) and HAQ-DI functional remission (score ≤0.5) were achieved from 12 weeks onwards in patients in all MTX dose groups (<8 mg; ≥8 to <10 mg; ≥10 to <12 mg; and ≥12 mg) and these results were sustained over 2 years, with no significant differences between MTX dose groups. Thus, concomitant tapered-dose MTX along with adalimumab over 2 years did not impact clinical response. The CONCERTO trial reported that rates of low disease activity as assessed by DAS28-CRP between patients treated with concomitant MTX doses of 10 and 20 mg/week and improvements in baseline HAQ-DI scores in patients treated with concomitant MTX doses of 2.5, 5, 10, and 20 mg/week at 26 weeks were not significantly different in patients with early RA receiving adalimumab treatment [16]. Improvements in DAS28 and HAQ-DI scores over 1 year in patients from the DREAM registry were also not significantly different in patients receiving concomitant MTX doses of 10, 15, and 20 mg/week [23].

Mean HAQ-DI scores from 12 weeks to 104 weeks were numerically higher for patients receiving ≥12 mg/week MTX compared with those receiving lower doses of MTX, thus suggesting that high-dose MTX was possibly maintained in some patients in an effort to achieve better quality of life in patients with a slower improvement in HAQ-DI scores.

Though the difference in mTSS score was not significant between the dose groups at week 104, it was numerically higher in the MTX <8 mg/week and ≥12 mg/week dose groups compared to that in the MTX 8–10 mg/week group. In the ≥12 mg/week group, this could suggest a similar effort, as discussed in the former paragraph, of trying to reduce the progression of bone destruction. For the <8 mg/week group, the sample size was very small (n = 5), which could have caused a bias in ΔmTSS at 104 weeks. It is noteworthy that the mean mTSS score at baseline, identified as a predictive factor for structural remission in the 52 week-results from this study [20], was numerically high in both MTX <8 mg/week and ≥12 mg/week groups.

No new safety concerns were identified with combination therapy in this study population with early RA and high disease activity. However, more non-serious ADRs were reported among patients in whom the MTX dose was tapered than in those whose dose was not tapered. In this study, non-serious hepatobiliary disorders were reported in 12 patients (8.8%) in the MTX-tapered group but in 0 patients in the group that did not undergo MTX tapering. In addition, of the 17 non-serious ADRs in the SOC ‘investigations’ in the MTX-tapered group, 13 were related to liver function. Hepatobiliary disorders are known dose-dependent ADRs of MTX treatment [24], and therefore, the MTX dose was possibly reduced in patients with deteriorated liver function. On the other hand, the incidence rate of infections and infestations was similar in the MTX-tapered and MTX non-tapered groups. The CONCERTO trial did not report an increase in the incidence of ADRs at higher MTX doses [16]. However, a higher incidence of elevated alanine aminotransferase was observed at the MTX 10-mg/week dose compared with incidences at other doses [16]. Interestingly, the incidence of ADRs over 28 weeks was significantly higher in patients receiving concomitant MTX at a dose of 0 to <4 mg/week compared with higher dose groups (>4; 4 to <6; 6 to <8; 8 to <10; and ≥10 mg/week) in the MELODY study [19]. However, it was speculated that this was because more patients in the 0- to <4-mg/week dose group were elderly, with comorbidities and a longer disease duration. The MUSICA trial compared low-dose (7.5 mg/week) MTX with high-dose (20 mg/week) MTX treatment following initiation of adalimumab therapy in patients with RA previously receiving MTX ≥15 mg/week with moderate to high disease activity as measured by DAS28-CRP [17]. This trial observed a higher incidence of ADRs over 24 weeks in patients who tapered to low-dose MTX; this was attributed this to disease flare following MTX dose reduction [17]. Thus, further analysis is required to ascertain the reasons for higher incidences of ADRs in the MTX dose-tapering group in our study.

The current study had several limitations: radiographic progression could only be assessed in a small number of patients because of the limited availability of joint X-rays in a real-world setting; also, real-world results are not directly comparable with results obtained from a randomized controlled trial setting. However, this study provides robust real-world data on the patterns of MTX dose tapering. The HAWK study results confirm the long-term effectiveness and safety of adalimumab with high-dose (≥12 mg/week) MTX in biologic-naïve Japanese patients with RA of <2 years’ duration in a real-world setting. Overall, 84.3% of patients who completed the 2-year study period maintained ΔmTSS of ≤1.0. The effectiveness of adalimumab treatment was maintained over a prolonged duration, as was evident from the increased number of patients discontinuing adalimumab in the latter part of the study because of improved symptoms. Over 2 years, the MTX dose was tapered in almost half of the patients and doses were reduced to <10 mg/week in about one-third of patients, without negatively impacting disease activity.

Conflict of interest

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

Tsuneyo Mimori has received grant and research support from Asahi Kasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Pfizer, Sanofi and Takeda and has received speaker fees from AbbVie, Chugai, Eisai, Mitsubishi Tanabe, and Pfizer.

Hisashi Yamanaka has received research grants from AbbVie GK, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Pfizer, Takeda, UCB, YL Bio, Teijin Pharma, Astellas, Ayumi, Eli Lilly, Novartis, Kaken, Nippon Shinyaku, Ono, Daiichi Sankyo, Taisho Toyama, Torii, and Asahi Kasei and has received consulting fees or speaker fees from AbbVie GK, Bristol-Myers Squibb, Chugai, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, YL Bio, Teijin Pharma, Astellas, AYUMI, Lilly, and Asahi Kasei.

Naomi Sunaga, Kazuo Morita, and Junko Kimura are full-time employees of AbbVie GK and may own AbbVie stock or stock options.

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 all the patients for their contribution to the study. We would also like 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.

Additional information

Funding

This study was funded by AbbVie GK and Eisai Co., Ltd. AbbVie GK and Eisai Co., Ltd. provided funding to EPS Corporation for data analysis. AbbVie participated in study design, the collection, analysis, and interpretation of the data and in drafting, review, and approval of the manuscript. 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 was provided by Dr. Deepali Garg, MBBS, PGDHA, of Cactus Communications and was funded by AbbVie GK and Eisai Co., Ltd.