Abstract
Objectives
To explore whether the duration of prior low-dose methotrexate treatment (MTX; ≤8 mg/week) influences the safety and effectiveness of high-dose MTX (>8 mg/week) in Japanese patients with rheumatoid arthritis (RA).
Methods
This post hoc sub-analysis of a Japanese post-marketing surveillance study evaluated patients initiating high-dose MTX with ≥1 year or <1 year prior low-dose MTX use. Over 24 or 52 weeks, adverse drug reactions (ADRs) were monitored, and effectiveness was assessed using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4 (ESR)].
Results
One thousand two hundred and ninety-two MTX ≥1 year and 1001 MTX <1 year patients were included. The incidence of ADRs during the 24- and 52-week follow-up period was significantly more frequent in MTX <1 year than ≥1 year patients and serious ADRs were significantly higher in MTX <1 year than ≥1 year patients during the 52-week follow-up period (all p < .05). Over both follow-up periods, the mean DAS28-4 (ESR) significantly decreased from baseline for all groups. Remission and low disease activity rates (DAS28-4 (ESR) <2.6 and <3.2, respectively) increased from baseline for all groups.
Conclusion
High-dose MTX reduced disease activity regardless of prior treatment duration, but ADRs occurred more frequently among MTX <1 year patients compared to MTX ≥1 year patients.
Introduction
Globally, the conventional synthetic disease-modifying antirheumatic drug (csDMARD) methotrexate (MTX) remains the gold standard and most widely used first-line therapy for rheumatoid arthritis (RA) [Citation1–3]. Patients typically receive initial MTX doses of 7.5–10 mg/week, with subsequent dose escalation up to 25 mg/week [Citation3].
In Japan, MTX was approved initially for the treatment of RA at a maximum dose of 8 mg/week, with the Ministry of Health, Labour and Welfare (MHLW) later approving doses of up to 16 mg/week, based on study data that suggested that higher doses could confer improved antirheumatic effects in Japanese populations [Citation4,Citation5]. In line with regulatory requirements mandated upon the approval of higher MTX doses, a post-marketing surveillance (PMS) study was implemented to evaluate the safety and effectiveness of high-dose MTX (>8 mg/week) in Japanese patients with RA in a real-world clinical setting [Citation6].
Primary analyses of the PMS study data indicated that high-dose MTX was well tolerated and improved disease control over both 24- and 52-week follow-up periods [Citation6]. It has previously been suggested that tolerance to MTX increases with duration of treatment [Citation7]. Notably, prior to the initiation of high-dose MTX, the mean duration of low-dose MTX treatment (≤8 mg/week) in the overall PMS study population was 31.4 months in the 24-week follow-up period (range: 0.0–296.0 months), and 24.3 months in the 52-week follow-up period (range: 1.0–211.0 months; data on file). As such, the favorable results observed with high-dose MTX in the overall PMS study population may have been influenced by the fact that some patients had previously received long-term low-dose MTX, potentially leading to greater overall tolerability and effectiveness. This hypothesis was further supported by risk factor analyses, which found that an MTX usage of ≥1 year decreased the risk of hepatic disorders in the overall PMS study population [Citation6].
Therefore, due to concerns that treatment with high-dose MTX may lead to increased adverse drug reactions (ADRs), and/or reduced effectiveness, specifically in patients with limited prior MTX treatment, a post hoc sub-analysis of the PMS study was conducted to compare the safety and effectiveness of high-dose MTX in Japanese patients with RA who had used MTX for ≥1 year or <1 year prior to treatment with high-dose MTX.
Materials and methods
Study design and patients
The PMS study (NCT01414257) was a multicenter, observational study conducted across Japan. The protocol for the PMS study was reviewed and approved by the MHLW, and the study was conducted in accordance with Good Post-Marketing Surveillance Practice.
The study design has been described previously [Citation6]. In brief, between 2011 and 2012, the study enrolled Japanese patients with RA starting with high-dose MTX (Rheumatrex® 2 mg capsule (Pfizer Japan Inc, Tokyo, Japan) at a dose of >8 mg/week) at the discretion of their prescribing physician. Patients were excluded if they had previously received high-dose MTX. Following enrollment, patients were followed for 24 or 52 weeks, with case report forms used to collect safety and effectiveness data. All patients in the 52-week follow-up period had continued from the 24-week follow-up period. Therefore, the 24-week follow-up period included data from both the 24- and 52-week patient populations collected between baseline and week 24. Over the course of the study, no restrictions were imposed on the use of concomitant RA therapies, including biologic DMARDs (bDMARDs).
This post hoc sub-analysis assessed the safety and effectiveness data that were collected during the 24- and 52-week follow-up periods for patients who had used MTX for ≥1 year at baseline (hereby referred to as MTX ≥1 year patients) and <1 year at baseline (hereby referred to as MTX <1 year patients). Also, the effectiveness and safety of high-dose MTX were analyzed in a subset of the <1 year patient subpopulation, who had used MTX for <6 months at baseline (hereby referred to as MTX <6 months patients).
Safety assessments
The safety population comprised patients who received ≥1 dose of the study drug (high-dose MTX) for the treatment of RA and attended ≥1 follow-up visit during the study period.
Data on all ADRs were collected and coded on an ongoing basis using the Medical Dictionary for Regulatory Activities Japanese Translation (MedDRA/J) Version 16.1. Serious ADRs were defined as those that resulted in death, were life-threatening, required in-patient hospitalization, resulted in persistent or significant disability/incapacity, or resulted in congenital anomalies/congenital disabilities. ADRs of special interest were hepatotoxicity, infections, hematopoietic disorders, interstitial lung disease, pulmonary fibrosis, renal disorders, and lymphomas.
For both the 24- and 52-week follow-up periods, statistical comparisons between the proportions of patients reporting ADRs and serious ADRs in MTX ≥1 year and MTX <1 year groups, were performed using a chi-squared test, with a significance level of p < .05. The incidences of ADR and serious ADR, by preferred term, were summarized descriptively and their incidence rates (patients with events per 100 patient-years) were evaluated. To explore the risk factors for ADRs of special interest, multivariate logistic regression analysis, using the stepwise method, was conducted, wherein demographic/baseline disease characteristic variables significant at p < .05 in a univariate model were assessed using multivariate models. This analysis was conducted for MTX ≥1 year and MTX <1 year patients only.
Effectiveness assessments
The effectiveness population comprised patients who had received ≥1 dose of the study drug (high-dose MTX) for the treatment of RA and who had evaluable disease activity, as measured by Disease Activity Score in 28 joints (four variables), erythrocyte sedimentation rate (DAS28-4 (ESR)).
Effectiveness was assessed by observing changes in DAS28-4 (ESR) every 4 weeks from baseline (prior to the initiation of high-dose MTX) up to 24 and 52 weeks. Differences in the mean DAS28-4 (ESR) at baseline and each evaluation time point were compared using a two-tailed paired t-test, with a significance level of p < .05.
In addition, based on the American College of Rheumatology cutoffs for DAS28 [Citation8], the proportions of patient achieving DAS28-4 (ESR)-defined remission (DAS28-4 (ESR) <2.6), low disease activity (LDA; DAS28-4 (ESR) ≥2.6 and <3.2), moderate disease activity (MDA; DAS28-4 (ESR) ≥3.2 and ≤5.1), or high disease activity (HDA; DAS28-4 (ESR) >5.1) were reported. For the 24-week follow-up, these were reported every 4 weeks from baseline to week 24, while for the 52-week follow-up period, these were reported at baseline and at week 52 only.
For all assessments, missing data were imputed using the last observation carried forward method, except for baseline values.
Results
Patients
A total of 2860 Japanese patients with RA were enrolled in the PMS study. Of the patients with prior MTX usage data from the PMS population, 1292 were MTX ≥1 year patients (safety population, n= 1283; effectiveness population, n= 1252) and 1001 were MTX <1 year patients (safety population, n= 991; effectiveness population, n= 981), with a follow-up period of 24 weeks (Supplementary Figure 1(a)). Of the 1001 MTX <1 year patients, 745 were also MTX <6 months patients (safety population, n= 737; effectiveness population, n= 729; Supplementary Figure 1(a)).
Following this period, 136 MTX ≥1 year patients (safety population, n= 135; effectiveness population, n= 134) and 141 MTX <1 year patients (safety population, n= 140; effectiveness population, n= 137) continued up to 52 weeks (Supplementary Figure 1(b)). Of the 141 MTX <1 year patients, 109 were also MTX <6 months patients (safety population, n= 108; effectiveness population, n= 105; Supplementary Figure 1(b)).
The demographic and baseline disease characteristics of the MTX ≥1 year and MTX <1 year patients, included in the 24- and 52-week follow-up periods, are summarized in . For both follow-up periods, MTX ≥1 year patients had longer RA disease duration and a higher disease functional class/stage (according to the Steinbrocker criteria) than MTX <1 year patients. Similarly, for both follow-up periods, a higher proportion of MTX ≥1 year patients had prior bDMARD and steroid use, and were receiving concomitant bDMARDs at baseline, than MTX <1 year patients.
Table 1. Demographic and baseline disease characteristics of the MTX ≥1 year patients and the MTX <1 year patients (safety population).
The demographic and baseline disease characteristics of MTX <6 months patients are summarized in Supplementary Table 1; generally, MTX <1 year and MTX <6 months patients, for both follow-up periods, were similar at baseline.
After the study started, 6.2% of MTX ≥1 year patients and 16.0% of MTX <1 year patients with 24 weeks of follow-up initiated bDMARD therapy. During the 52-week follow-up period, this applied to 8.9% and 26.4% of MTX ≥1 year patients and MTX <1 year patients, respectively. Among the patients included in the 24-week follow-up period, concomitant (baseline or initiated during study) folic acid, steroids and/or csDMARDs (non-MTX) were reported in 80.0%, 47.6%, and 32.0% of MTX ≥1 year patients, and 84.8%, 46.5%, and 20.0% of MTX <1 year patients, respectively. During the 52-week follow-up period, this applied to 91.9%, 53.3%, and 33.3% of MTX ≥1 year patients, and 92.9%, 52.9%, and 25.0% of MTX <1 year patients, respectively.
In the safety population, treatment was discontinued by 148/1283 (11.5%) MTX ≥1 year patients and 163/991 (16.4%) MTX <1 year patients (including 122 MTX <6 months patients) during the 24-week follow-up period. In total, 29/135 (21.5%) MTX ≥1 year patients and 48/140 (34.3%) MTX <1 year patients (including 35 MTX <6 months patients) discontinued treatment during the 52-week follow-up period.
Safety
Overall safety
A total of 67 and 8 MTX ≥1 year patients and 68 and 24 MTX <1 year patients discontinued due to ADRs during the 24- and 52-week follow-up periods, respectively. The ADR profiles of the MTX ≥1 year patients and the MTX <1 year patients in the 24- and 52-week follow-up periods are summarized in .
Table 2. Summary of the (a) ADRs and (b) serious ADRs reported by MTX ≥1 year patients and MTX <1 year patients (safety population).
During the 24-week follow-up period, the proportion of patients experiencing ADRs was significantly lower for MTX ≥1 year patients than MTX <1 year patients (16.84% vs. 28.25%, respectively; p < .001). In each subpopulation, the most common ADRs, by system organ class (SOC), were hepatobiliary disorders; these were numerically higher in MTX <1 year patients than MTX ≥1 year patients (15.14% vs. 6.24%, respectively). Of hepatobiliary disorders, the most frequent was abnormal hepatic function, which was substantially higher in MTX <1 year patients than MTX ≥1 year patients (11.81% vs. 4.75%, respectively). The proportion of patients reporting other ADRs was generally similar between the subpopulations.
During the 24-week follow-up period, there was no significant difference in the proportion of patients reporting serious ADRs between the MTX ≥1 year patients and the MTX <1 year patients (1.33% vs. 1.82%, respectively; p=.3453). In both subpopulations, the most common serious ADRs, by SOC, were infections and infestations, with pneumonia being the most frequently reported infection. Additionally, there was one treatment-related death due to Pneumocystis jirovecii pneumonia in the MTX <1 year population and one death due to pneumonia in the MTX ≥1 year population which was not considered treatment-related.
During the 52-week follow-up period, the total proportion of patients reporting ADRs was significantly lower in MTX ≥1 year patients than MTX <1 year patients (28.15% vs. 46.43%, respectively; p < .01). As observed in the 24-week follow-up period, the most common ADRs, by SOC, were hepatobiliary disorders; the incidences of these were numerically lower in MTX ≥1 year patients than MTX <1 year patients (7.41% vs. 22.14%, respectively). Of the hepatobiliary disorders, the most frequent was abnormal hepatic function; the incidences of this ADR were substantially lower in MTX ≥1 year patients than MTX <1 year patients (5.93% vs. 17.14%, respectively). Across the other reported ADRs, the incidences were generally similar between the subpopulations.
In contrast to the 24-week follow-up period, the proportion of patients reporting serious ADRs was significantly lower in MTX ≥1 year patients than MTX <1 year patients (0.74% vs. 5.00%, respectively; p < .05). Similar to the 24-week follow-up period, the most common serious ADRs, by SOC, were infections and infestations; a single MTX ≥1 year patient reported both a urinary tract infection and bacterial pneumonia, while in the MTX <1 year patients, pneumonia and Pneumocystis jirovecii pneumonia were the most frequently reported infections.
When liver-related ADRs were analyzed according to MTX dose at the onset, the highest proportion of patients reporting ADRs was observed at the 10 mg dose for both the MTX ≥1 year and MTX <1 year subpopulations over the 24-week and 52-week follow-up periods (Supplementary Table 2). A relatively high proportion of patients reporting ADRs was also observed with the 12 mg dose for both the MTX ≥1 year and MTX <1 year patients over both follow-up time periods. Generally, the proportion of patients reporting ADRs was numerically lower in MTX ≥1 year patients than MTX <1 year patients for both follow-up periods and at all doses of MTX, with the exception of <10 mg at the 24-week follow-up. The most frequently reported ADRs were related to hepatobiliary disorders, specifically abnormal liver function. The proportion of patients reporting other liver-related ADRs was generally low throughout.
During the 24-week and 52-week follow-up periods, the incidences and types of ADR/serious ADR reported by the MTX <6 months patients were similar to those reported by the MTX <1 year patients (Supplementary Table 3).
Risk factors for the ADRs of special interest
All demographic/baseline disease characteristic variables identified as risk factors for the ADRs of special interest for the MTX ≥1 year patients and the MTX <1 year patients are summarized in .
Table 3. Risk factors for (a) hepatotoxicity, (b) infections, (c) serious infections, and (d) hematopoietic disorders in MTX ≥1 year patients and MTX <1 year patients (safety population).
For both patient groups, and for both follow-up periods, the presence of hepatic function disorder was significantly associated with an increased risk of hepatotoxicity ADRs. For the MTX ≥1 year patients during the 24-week follow-up period, a BMI ≥25 kg/m2 was also associated with an increased risk of hepatotoxicity. Comorbid chronic infections, opportunistic infections (current or a history of), and the presence of diabetes mellitus were risk factors for infection ADRs, with opportunistic infections identified as a risk for serious infections specifically. Infections reported by ≥5 patients and included as risk factors in the analysis were: tuberculosis (including pulmonary and latent), chronic bronchitis, atypical mycobacterial infections, herpes zoster, chronic sinusitis/sinusitis and Pneumocystis jirovecii pneumonia. A white blood cell count <4000/µL before administration was associated with an increased risk of hematopoietic disorders, while a Steinbrocker’s class 3 and 4 was associated with a decreased risk in these patients.
For the MTX <1 year patients during the 24-week follow-up period, the other factors associated with an increased risk of hepatotoxicity were an ALT level ≥40 IU/L before administration and concomitant folic acid use, while ages ≥65 years old were associated with a decreased risk. Factors associated with an increased risk of infections were comorbid chronic infections, opportunistic infections, and an albumin level <3.5 g/dL before administration. Steroid use and opportunistic infections were associated with an increased risk of serious infections. A lymphocyte count <1500/µL before administration and a platelet count <15 × 104/µL before administration were associated with an increased risk of hematopoietic disorders.
For the MTX ≥1 year patients during the 52-week follow-up period, the other risk factor associated with hepatotoxicity was an AST level ≥40 IU/L before administration. There were no factors significantly associated with either an increased or decreased risk of serious/opportunistic infections or hematopoietic disorders in these patients.
For the MTX <1 year patients during the 52-week follow-up period, a Steinbrocker’s class 3 and 4 was associated with an increased risk for infections, while opportunistic infections were associated with a substantially increased risk of serious infections. As with the MTX ≥1 year patients, there were no factors significantly associated with either an increased or decreased risk of hematopoietic disorders in these patients.
Few patients reported ADRs relating to interstitial lung disease, pulmonary fibrosis, renal disorders, and lymphomas during the 24- and 52-week follow-up periods (n≤ 6 per ADR). Therefore, these ADRs of special interest were not analyzed further.
Effectiveness
For both the MTX ≥1 year and MTX <1 year patients, the mean DAS28-4 (ESR) scores decreased from baseline with high-dose MTX across the 24- and 52-week follow-up periods ().
Figure 1. The mean (±SD) DAS28-4 (ESR) scores at 4-week time intervals during the (a) 24-week follow-up period and the (b) 52-week follow-up period (effectiveness population). *p<.05; **p<.001; ***p≤.0001 vs. baseline, paired t-test; last observation carried forward. DAS28-4 (ESR): Disease Activity Score in 28 joints, erythrocyte sedimentation rate; MTX: methotrexate; SD: standard deviation.
During both follow-up periods, despite the MTX <1 year patients reporting numerically higher mean DAS28-4 (ESR) scores than the MTX ≥1 year patients at baseline, by week 4, the mean scores were similar between the patient groups; these similarities were maintained through all subsequent time points.
Over the 24-week follow-up period, the mean (±standard deviation (SD)) DAS28-4 (ESR) scores decreased from 3.94 (±1.21) at baseline to 3.23 (±1.23) in the MTX ≥1 year patients, and from 4.33 (±1.26) at baseline to 3.18 (±1.24) in the MTX <1 year patients. From week 4 through week 24, the mean DAS28-4 (ESR) scores at each time point were significantly reduced than those at baseline in both subpopulations (all p < .001).
During the 52-week follow-up period, the mean (±SD) DAS28-4 (ESR) scores decreased from 3.66 (±1.24) at baseline to 2.76 (±1.01) in the MTX ≥1 year patients, and from 4.18 (±1.27) at baseline to 2.77 (±1.15) in the MTX <1 year patients. From week 4 through week 52, the mean DAS28-4 (ESR) scores at each time point were reduced significantly than those at baseline in both subpopulations (all p < .001, except the MTX ≥1 year patients at week 4 when p=.0127). Similar trends were observed with the MTX <6 months patients for both follow-up periods (Supplementary Figure 2).
In addition, during both the 24- and 52-week follow-up periods, the proportion of MTX ≥1 year and MTX <1 year patients in remission (DAS28-4 (ESR)) increased from baseline with high-dose MTX ().
Figure 2. The proportion of MTX ≥1 year patients and MTX <1 year patients achieving DAS28-4 (ESR)-defined remission (<2.6), LDA (≥2.6 and <3.2), MDA (≥3.2 and ≤5.1), or HDA (>5.1) during the (a) 24-week follow-up period (shown every 4 weeks from baseline to week 24) and the (b) 52-week follow-up period (shown at baseline and week 52) (effectiveness population). DAS28-4 (ESR): Disease Activity Score in 28 joints, erythrocyte sedimentation rate; HDA: high disease activity; LDA: low disease activity; MDA: moderate disease activity; MTX: methotrexate.
Over the 24-week follow-up period, remission rates increased from 13.0% to 33.6% in the MTX ≥1 year patients, and from 7.1% to 34.1% in the MTX <1 year patients (). Notably, despite a higher proportion of MTX ≥1 patients being in remission at baseline than MTX <1 year patients, remission rates between patient groups were similar as early as week 4. In a subgroup of patients who achieved remission during the 24-week follow-up, who were not receiving concomitant treatment with bDMARDs, and for whom the final MTX dose data were available, substantially higher proportion of both the MTX ≥1 year patients and the MTX <1 year patients were receiving MTX 10 mg/week, than the other doses ().
Figure 3. Final MTX dose breakdown among a subgroup of MTX ≥1 year patients and MTX <1 year patients who were not receiving concomitant bDMARDs and who achieved DAS28-4 (ESR)-defined remission (<2.6) during the (a) 24-week follow-up period and the (b) 52-week follow-up period. DAS28-4 (ESR): Disease Activity Score in 28 joints, erythrocyte sedimentation rate; MTX: methotrexate; n: number of patients receiving each dose.
Over the 52-week follow-up period, remission rates increased from 20.5% to 49.4% in the MTX ≥1 year patients, and from 11.3% to 44.3% in the MTX <1 year patients (). In contrast to the trends observed during the 24-week follow-up period, the remissions rates generally remained numerically higher in the MTX ≥1 year patients than the MTX <1 year patients through week 28; at all subsequent time points, the remission rates were generally similar (data not shown). Similar to the 24-week follow-up period, in a subgroup of patients who achieved remission during the 52-week follow-up period, who were not receiving concomitant treatment with bDMARDs, and for whom final MTX dose data were available, a higher proportion of MTX ≥1 year patients received MTX 10 mg/week than the other doses. However, for the MTX <1 year patients who achieved remission, a greater proportion received MTX ≤8 mg/week than the other doses ().
The proportion of patients with LDA (DAS28-4 (ESR) ≥2.6 and <3.2) also increased from baseline during both follow-up periods (). Over the 24-week follow-up period, the LDA rate increased from 14.1% to 20.0% in the MTX ≥1 year patients, and from 12.1% to 20.7% in the MTX <1 year patients. During the 52-week follow-up period, LDA rates increased from 13.3% to 24.1% in the MTX ≥1 year patients, and from 10.3% to 25.8% in the MTX <1 year patients.
Remission and LDA rates in the MTX <6 months patients were similar to those observed in the MTX <1 year patients across both follow-up periods (Supplementary Figure 3).
Discussion
While primary analyses of the PMS data indicated that high-dose MTX was well tolerated and improved disease activity in Japanese patients with RA [Citation6], there were concerns that the positive results seen in the overall PMS study population were skewed by some patients having received prior long-term low-dose MTX treatment. With this in mind, this post hoc sub-analysis of the PMS data compared the safety and effectiveness of high-dose MTX in patients with ≥1 year than <1 year and/or <6 months prior low-dose MTX treatment, to explore whether previous MTX treatment duration influenced the frequency of ADRs or changes in RA disease activity. Overall, the findings of this sub-analysis support the safety and effectiveness of high-dose MTX in Japanese patients with RA, regardless of prior low-dose MTX treatment duration.
The types of ADR observed in this sub-analysis were similar to those reported for the overall PMS study population [Citation6] and to those observed in prior PMS studies of low-dose MTX (data on file). Furthermore, during both the 24- and 52-week follow-up periods, the incidences of serious ADR in MTX <6 months, MTX <1 year, and MTX ≥1 year patients were generally similar to those observed in the overall PMS study population [Citation6]. An exception to this was the MTX <1 year patients in the 52-week follow-up period, in whom the incidence of all serious ADRs was almost double that observed during the same period in the overall PMS study population (5.00% vs. 2.69%, respectively); whereas, MTX ≥1 year patients demonstrated a lower incidence of serious ADRs over the 52-week period, compared to the overall PMS study population (0.74% vs. 2.69%, respectively). Looking specifically at the serious ADRs of special interest during this follow-up period, the proportion of patients reporting pneumonia and interstitial lung disease were numerically higher in the MTX <1 year patients than those observed in the overall PMS study population (1.43% vs. 0.60%, and 0.71% vs. 0.30%, respectively) [Citation6]. There were no reports of these serious ADRs occurring in the MTX ≥1 year patients. Furthermore, during the 24- and 52-week follow-up periods, the incidences of all ADRs in the MTX <1 year patients (28.3% and 46.4%, respectively) and the MTX <6 months patients (29.7% and 45.4%, respectively) were numerically higher than those observed in the overall PMS study population (21.4% and 35.5%, respectively) [Citation6] or the MTX ≥1 year patients (16.8% and 28.2%, at the 24- and 52-week follow-up periods, respectively). Notably, when the ADRs were evaluated by SOC, the proportion of patients reporting hepatobiliary disorders during the 24- and 52-week follow-up periods were found to be higher in the MTX <1 year patients (15.1% and 22.1%, respectively), and the MTX <6 months patients (16.2% and 25.0%, respectively), but were lower in the MTX ≥1 year patients (6.2% and 7.4%, respectively) than the overall PMS study population (9.6% and 13.7%, respectively) [Citation6]. Together, these observations suggest that ADRs occur more frequently in patients with short-term (<1 year) low-dose MTX treatment than in patients with prior long-term (≥1 year) low-dose MTX treatment. Previous studies of MTX in patients with RA have reported similar observations; notably, in a long-term tolerability study, major toxicity was predominantly observed over the first 12 months of treatment with MTX exceeding 15 mg/week [Citation7], and a systematic literature review reported that 79% of infections over 3 years of treatment occurred in the first 2 years of MTX treatment [Citation9].
Although the risk factors for the ADRs of special interest observed in this sub-analysis were generally consistent with those observed in the overall PMS study population [Citation6], some additional risk factors (associated with both an increased and decreased risk for ADRs of special interest) were identified in the MTX <1 year patients. Notably, concomitant treatment with folic acid was associated with an increased risk of hepatotoxicity in MTX <1 year patients during the 24-week follow-up. Given that folic acid is known to be useful for reducing the incidence of hepatotoxicity [Citation10], and is globally recommended for patients with RA receiving MTX treatment [Citation11,Citation12], this result is surprising. One possible explanation is that folic acid was being administered to patients who had developed or were developing hepatic dysfunction. Approximately, 80% of patients in the MTX <1 year population received concomitant folic acid. However, this was not identified as a risk factor at the 52-week follow-up period for the same population or for the MTX ≥1 year patients at either follow-up period, suggesting that hepatotoxicity may be specific to patients with relative short-term MTX and concomitant folic acid use. Age ≥65 years was associated with a decreased risk of hepatotoxicity while Steinbrocker’s class 3 and 4 was associated with decreased risk of hematopoietic disorders. These observations are contrary to those expected in these populations but may be underpinned by proactive folic acid use in patients aged ≥65 years or those considered to be in high risk groups. In addition, platelet count of <15 × 104/µL and an albumin level of <3.5 g/dL, prior to high-dose MTX administration, were associated with an increased risk of hematopoietic disorders, and infections, respectively, while a history of steroid use was associated with an increased risk of serious infections. Prior studies have shown that hypoalbuminemia is associated with increased MTX-induced pulmonary and hematologic toxicity [Citation13,Citation14], and therefore support the hypothesis that baseline albumin may affect patients’ susceptibility to ADRs with MTX treatment.
With regard to the effectiveness data, reductions in mean DAS28-4 (ESR) and increases in the rates of remission and LDA from baseline, over the 24- and 52-week follow-up periods, were generally similar in this sub-analysis and the overall PMS study population [Citation6]. High-dose MTX appeared to confer rapid improvements in disease activity, with the greatest reductions in mean DAS28-4 (ESR) score observed at week 4, across both the 24- and 52-week follow-up periods for MTX <6 month and MTX <1 year patients. Notably, at week 4, the mean DAS28-4 (ESR) scores for patients with <1 year prior MTX use were similar to those observed in the overall PMS population [Citation6], despite the fact that the patients in this sub-analysis had numerically higher mean DAS28-4 (ESR) scores at baseline (for the 24- and 52-week follow-up periods, respectively; the mean DAS28-4 (ESR) scores at baseline were 4.4 and 4.3 for the MTX <6 months patients, 4.3 and 4.2 for the MTX <1 year patients, and 4.1 and 3.9 for the overall PMS study population). While significant decreases from baseline in mean DAS28-4 (ESR) were observed at week 4 in the MTX ≥1 year patients at both follow-up time periods, the greatest reductions were observed at week 8. The baseline mean DAS28-4 (ESR) scores were generally lower in the MTX ≥1 year patients than those in the MTX <1 year patients at both the 24- and 52-week follow-up periods (3.9 vs. 4.3 and 3.7 vs. 4.2, respectively), an effect likely underpinned by the long-term low-dose MTX treatment in the MTX ≥1 year subpopulation. However, the DAS28-4 (ESR) scores between these subpopulations were similar at all other assessment time points for both the 24- and 52-week follow-up periods. Furthermore, during the 24-week follow-up period of this sub-analysis, the LDA and remission rates at week 4 were similar to those observed in the overall PMS population [Citation6], despite MTX <6 months and MTX <1 year patients demonstrating a numerically higher proportion of patients with HDA at baseline (26.3% of the MTX <1 year patients, 30.0% of the MTX <6 months patients, 17.8% of the MTX ≥1 year patients, and 20.9% of patients in the overall PMS study population). Similar LDA and remission rates were generally maintained up to week 24; however, the MTX ≥1 year patients demonstrated marginally higher remission rates at week 4 and week 8 compared to the MTX <1 year patients and the overall PMS study population [Citation6] (these data were not reported for the 52-week follow-up period of the overall PMS study population, so we are unable to draw comparisons over this time period). Together, these findings suggest that prior long-term, low-dose MTX use may have little bearing on the effectiveness of high-dose MTX for the treatment of RA.
Data from the overall PMS study population [Citation6] and this sub-analysis suggest that high-dose MTX confers rapid effectiveness, irrespective of prior MTX treatment history. Interestingly, a 2009 systematic literature review of MTX data reported that the greatest clinical efficacy is seen in studies where MTX dose is rapidly escalated [Citation15]. In a subset of MTX ≥1 year and MTX <1 year patients who were not receiving concomitant bDMARDs, 95.1% and 87.2% of patients who achieved DAS28-4 (ESR) remission at the 24-week follow-up, respectively, were receiving MTX doses ≤12 mg/week, with the largest proportion of patients achieving remission receiving the 10 mg/week dose. Interestingly, at this follow-up period, the largest proportions of MTX ≥1 year patients and MTX <1 year patients reporting ADRs were receiving the 10 mg/week dose at the ADR onset, albeit the proportion of patients reporting ADRs was numerically lower in the MTX ≥1 year patients than the MTX <1 year patients (5.5% vs. 10.1%, respectively). In a subset of MTX ≥1 year and MTX <1 year patients who were not receiving concomitant bDMARDs, 96.0% and 76.5% of patients who achieved DAS28-4 (ESR) remission, respectively, at the 52-week follow-up period were receiving MTX doses ≤12 mg/week. The highest proportion of MTX ≥1 year patients and MTX <1 year patients achieving DAS28-4 (ESR) remission received 10 mg/week and ≤8 mg/week, respectively; however, such observations should be interpreted with caution given the low sample size at this follow-up period. Again, the highest proportions of patient reporting ADRs were receiving the 10 mg/week dose at the ADR onset, with the proportion of patients reporting ADRs being numerically lower in the MTX ≥1 year patients than the MTX <1 year patients (6.7% vs. 15%, respectively). Collectively, the high proportions of patients achieving DAS28-4 (ESR) remission at MTX doses ≤12 mg support the current MTX treatment guidelines in Japan that recommend doses up to 10–12 mg/week in patients with RA [Citation16].
The PMS study did have several limitations, which have previously been described [Citation6]. An additional limitation of this sub-analysis was that most patients were only followed for 24 weeks. The relatively limited patient numbers in the 52-week follow-up period mean that the corresponding results should be viewed with caution. Furthermore, a large proportion of the MTX <1 year patients also qualified as MTX <6 month patients, which likely underpins the similar observations between these two subpopulations and limits the identification of any differences between these prior low-dose MTX treatment periods. It is also worth noting that there were some differences in the demographics and baseline disease characteristics of the patients in this sub-analysis of MTX ≥1 year vs. MTX <1 year patients, and compared with those in the overall PMS study population, reflecting the real world setting. For the 24- and 52-week follow-up periods, the MTX <1 year patients and MTX <6 months were younger and had slightly higher disease severity compared to the overall PMS study population and the MTX ≥1 year patients, which is expected given the short duration of MTX treatment in these subpopulations. Mean RA durations were also lower in both the MTX <1 year patients and the MTX <6 months patients (approximately 3 years) than the overall PMS study population (approximately 7 years) [Citation6], while the MTX ≥1 year patients had substantially longer mean RA durations (approximately 9 years). In addition, prior steroid and bDMARD use was lower in the MTX <1 year patients and the MTX <6 months patients, compared with the overall PMS study population [Citation6], which is likely due to the shorter RA disease duration in these subpopulations.
Overall, this sub-analysis indicates that high-dose MTX was generally well tolerated and resulted in rapidly reduced disease activity in Japanese patients with RA, who had previously received low-dose MTX treatment. While the ADR profile was generally similar between all subpopulations, the overall incidence of ADRs was significantly higher in MTX <1 year patients than MTX ≥1 year patients at both follow-up time points, which supports the hypothesis that MTX tolerability increases with treatment duration. In contrast, improvements in disease activity and remission rates were similar between all subpopulations, regardless of prior low-dose MTX treatment duration. Taken together, these results suggest that high-dose MTX could be initiated in Japanese patients, with benefits in terms of effectiveness and minimal safety concerns, irrespective of the duration of prior low-dose MTX treatment.
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The authors thank all the physicians and patients who participated in this PMS study. The PMS study was sponsored and implemented by Pfizer Japan Inc, on behalf of the manufacturers of MTX, which included Sawai Pharmaceutical Co Ltd, Shiono Chemical Co Ltd, Mitsubishi Tanabe Pharma Corporation, Towa Pharmaceutical Co Ltd, and Sandoz Co Ltd According to the Pharmaceutical Affairs Law of Japan and the regulations promulgated thereunder, the Sponsor (Pfizer) was required to conduct a PMS study as a condition for the marketing approval of high-dose MTX 8–16 mg/week for RA. Pfizer was responsible for the development of the study protocol (with instructions from the Pharmaceuticals and Medical Devices Agency) and for the analysis of the study data. Medical writing support, under the direction of the authors, was provided by Kirsten Woollcott, MSc, and Robert Morgan, MSc, CMC Connect, McCann Health Medical Communications, and was funded by Pfizer Japan Inc., Tokyo, Japan, in accordance with Good Publication Practice (GPP3) Guidelines [Ann Intern Med. 2015;163:461–4].
Conflict of interest
Y. Suzuki has received research funding from Chugai Pharmaceutical Co Ltd, Teijin Pharma Ltd, Asahi Kasei Pharma Co, and has received speaking fees and/or honoraria from Eisai Co Ltd, Ono Pharmaceutical Co Ltd, Mitsubishi Tanabe Pharma Co Ltd, Maruho Co Ltd, GlaxoSmithKline K.K. and Pfizer Japan Inc. T. Hirose, N. Sugiyama, K. Nomura, and E. Campos Alberto are employees and shareholders of Pfizer Japan Inc.
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Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
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