Methotrexate use and risk of abnormal alanine aminotransferase elevation in children with rare inflammatory diseases: a self-controlled case series analysis using a pediatric electronic health record database in Japan

Abstract

Background:

Methotrexate (MTX) is commonly prescribed for pediatric inflammatory diseases. However, clinical data on MTX-induced liver injury in children with rare inflammatory diseases currently remain limited.

Objectives:

To examine the association between MTX treatment and abnormal liver function in children with inflammatory diseases and to characterize the clinical course of suspected MTX-induced liver injury cases.

Design:

A self-controlled case series analysis.

Methods:

This study was conducted on children aged <15 years with juvenile idiopathic arthritis, psoriasis, or inflammatory bowel disease between April 2016 and March 2024. Data were obtained from the Pediatric Medical Information Collection System database, which integrates electronic medical records from over 40 pediatric medical institutions in Japan. The risk period was defined as the 7-day interval following MTX administration. In addition, this analysis compared the incidence of outcomes during the risk period with the baseline period within the same individuals. The outcome was alanine aminotransferase (ALT) elevation, defined as serum ALT levels exceeding three times the upper limit of normal. The age-adjusted incidence rate ratio (aIRR) was calculated, and clinical courses were assessed following ALT elevation.

Results:

Among 3696 children with inflammatory diseases, 587 received MTX treatment, while 81 developed abnormal ALT elevation. An increased risk of ALT elevation was observed (aIRR: 2.27, 95% confidence interval: 1.45–3.55). Among 45 patients with ALT elevation observed during the risk period, the normalization occurred in 35 patients. The 11 patients experienced a relapse of ALT elevation, while no patients receiving folic acid supplementation showed a relapse of ALT elevation.

Conclusion:

Methotrexate treatment in children with inflammatory diseases increases the risk of liver enzyme elevation, highlighting the necessity of liver function monitoring. Folic acid supplementation may help mitigate the exacerbation of MTX-induced liver injury in pediatric patients.

Plain language summary

Elevated liver enzymes following methotrexate administration in children with rare inflammatory diseases

Why was the study done? Methotrexate is administered for the treatment of cancer and inflammatory diseases. However, only a few studies have examined the incidence of abnormal liver function test results associated with methotrexate use, while reports on the clinical course in children with rare inflammatory diseases are similarly lacking.

What did the researchers do? The researchers investigated the association between methotrexate treatment and elevated liver enzyme levels in children with inflammatory diseases using pediatric health records database and a self-controlled case series analysis. Additionally, children with elevated alanine aminotransferase levels during methotrexate treatment were studied in the clinical course of suspected methotrexate-induced liver injury cases.

What did the researchers find? Among the 81 children with inflammatory diseases who received methotrexate treatment, approximately twice the risk of elevated liver enzymes was observed. Among patients developed an elevated liver enzymes during methotrexate treatment, most patients had normalization of liver enzymes, and the time to the normalization was shorter among patients who received hepatoprotective medications than among those who received non-pharmacologic management. While some patients had a relapse of elevated liver enzyme or elevated total bilirubin, while no patients receiving folic acid supplementation showed a relapse of alanine aminotransferase elevation or elevated total bilirubin.

What do the findings mean? This research has identified an increased risk of abnormal liver enzyme elevation during methotrexate treatment in children with inflammatory diseases. These findings emphasize the importance of liver function monitoring to prevent the exacerbation of liver dysfunction in children treated with methotrexate and the potential of folic acid supplementation as a strategy for preventing the exacerbation of methotrexate-induced liver injury.

Keywords

alanine aminotransferase liver function methotrexate pediatric inflammatory disease

Introduction

Methotrexate (MTX), a folic acid antagonist, is administered for the treatment of cancer and inflammatory diseases. Low-dose MTX is used to manage inflammatory conditions such as rheumatoid arthritis, juvenile idiopathic arthritis (JIA), psoriasis, Crohn’s disease, and arthritis associated with ulcerative colitis.^1–5 However, MTX exposure has been associated with liver injury, which primarily presents as acute hepatotoxicity.^6,7 Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels serve as indicators of hepatotoxicity. AST levels lack specificity for liver injury, as an increase in AST levels is also associated with inflammatory diseases of various organs, including the lungs, kidneys, and heart. By contrast, ALT is a liver-specific marker.⁸

Although the association between MTX use and abnormal ALT elevation has previously been reported,^7,9–11 most investigations have focused on adult populations, and reports demonstrating this association in pediatric patients remain limited.^12,13 Pediatric drug-induced liver injury presents with distinct clinical features and causes, attributable to immaturity of the pediatric liver and differences in medication profiles compared with those of adults,¹⁴ although some reports on signal detection have helped identify MTX as a potential cause of liver injury in pediatric patients with inflammatory diseases and cancer.^15,16 Given this context, further research on pediatric MTX-associated liver injury is required. Furthermore, there are currently no reports on the clinical course of children with abnormal ALT elevation following MTX administration, including normalization of liver function, relapse of elevated ALT levels, or medical management. We previously reported that pediatric patients with inflammatory disease and cancer receiving MTX treatment experienced ALT elevation and relapse, thereby emphasizing the importance of liver function monitoring in pediatric clinical practice.¹⁷

The incidence of JIA, Crohn’s disease, ulcerative colitis, and psoriasis in children is approximately 10, 4, and 11 per 100,000 children in Japan, respectively, and 40.8 per 100,000 children in the United States. Thus, these pediatric inflammatory diseases are uncommon.^1,18–20 Investigating this association in rare diseases presents challenges, as traditional study designs with comparison groups often fail to account for inter-individual variability owing to small sample sizes. By contrast, self-controlled case series (SCCS) study designs help to effectively control for time-invariant confounders, including genetic factors, regardless of whether these factors were measured.^21,22 Furthermore, these studies are well-suited to adjust for variations in prescription drug use patterns and outcome characteristics related to underlying pediatric disease. In addition, this design has many advantages over cohort studies in efficiently evaluating associations with exposures and outcomes, even if the proportion of cases attributable to exposure is small.²¹ Thus, SCCS analysis can be applied to drug safety analyses in low-prevalence diseases, given the small sample sizes. Therefore, in this study, we employed an SCCS design, a case-only approach, to evaluate the association between MTX administration and abnormal ALT elevation in pediatric patients with rare inflammatory diseases, such as JIA, inflammatory bowel disease (IBD), and psoriasis. Furthermore, we characterized the clinical course of patients following ALT elevation in those undergoing MTX treatment. These findings may help in optimizing MTX treatment strategies and liver function monitoring in pediatric patients with inflammatory diseases.

Methods

Data source and study setting

In this study, we utilized electronic health record data from the Pediatric Medical Information Collection System (P-MICS) database in Japan. The P-MICS was established in 2012 by the Ministry of Health, Labour and Welfare in collaboration with the National Center for Child Health and Development to support the appropriate use and clinical development of pediatric medicines. As of March 2024, the database includes anonymized records of over 1.3 million patients from 43 facilities, comprising 11 hospitals and 32 clinics.²³ The database covers approximately 50% of children’s hospitals, including approximately 25% of the total number of hospitals that provide the majority of pediatric services in Japan. The data were derived from a Japanese pediatric hospital; thus, these results may be generalizable to pediatric patients receiving MTX treatment in a similar healthcare setting. The P-MICS collects information on patient demographics, medical diagnoses coded according to the International Classification of Diseases, 10th Revision (ICD-10), prescription records based on Anatomical Therapeutic Chemical and YJ codes, and laboratory test results categorized under the Japan Laboratory Code 10.²⁴ Liver function test data were available in this database for analysis.

Study population and period

In this study, we included pediatric patients diagnosed with JIA, IBD, or psoriasis, for whom MTX was prescribed as treatment. Pediatric patients seen at hospitals and aged <15 years with confirmed ICD-10-coded diagnoses between April 1, 2016, and March 31, 2024, were included. Supplemental Table 1 provides the diagnosis code list.

The observation period began at the time of initial diagnosis of the target diseases and ended at (i) the first occurrence of ALT elevation, (ii) 365 days after the diagnosis, or (iii) the last available medical record. To maximize the sample size, exclusion criteria were limited. Patients were excluded when ALT levels were not measured. In addition, patients treated in clinics were excluded, as hospital-based patients undergo continuous ALT monitoring within the same facility, whereas clinic-based patients may be transferred, preventing confirmation of observation periods.

Self-controlled case series

An SCCS design was followed to examine the association between MTX treatment and ALT elevation. This design compared the incidence of outcomes during the exposure period with the non-exposure period within the same individuals who experienced both exposures and outcomes, thereby automatically adjusting for known and unmeasured time-invariant confounders that vary among individuals.

Exposure and outcome definitions

The SCCS design applied in this study is illustrated in Figure 1. Exposure was defined as the administration of injectable or oral MTX formulations based on prescription records in P-MICS. Supplemental Table 2 lists the MTX prescription codes.

Figure 1.

Overview of the design of this self-controlled case series.

The risk period extended from the date of the MTX prescription to 7 days after the final dose. The baseline period comprised the remainder of the observation period, excluding the risk period. All ALT test values measured during the observation period were included in the analysis. The outcome measure was ALT elevation, defined as ALT levels exceeding three times the upper limit of normal (ULN). ALT, rather than AST, was selected as the primary marker, given its enhanced specificity for liver function. Since initial ALT elevation may influence subsequent ALT abnormalities, the first occurrence of ALT elevation was analyzed separately.²¹ Total bilirubin (TB) elevation, defined as serum TB >2 × ULN following ALT elevation, was assessed as an indicator of moderate or high liver injury severity. ULN values for liver function tests were derived from reference values established in a study conducted at the National Center for Child Health and Development.²⁵

Clinical course and management

Herein, we examined the clinical courses following initial ALT elevation during MTX treatment, including MTX re-prescription, ALT normalization (ALT < ULN), relapse of ALT elevation, and TB elevation. Several management strategies for MTX-induced liver injury have thus far been implemented in clinical practice. The management approaches used for patients in the present study were investigated based on clinical course data. In addition, we analyzed pharmacotherapy for liver injury, including prescriptions for folic acid, glycyrrhizic acid (monoammonium glycyrrhizate, glycine, and l-cysteine hydrochloride or monoammonium glycyrrhizate, glycine, and dl-methionine), and ursodeoxycholic acid. The Japanese guideline for MTX use in patients with rheumatoid arthritis suggests folic acid administration for MTX-related adverse events.³ In addition, the Japanese manual for serious adverse events recommends the administration of glycyrrhizic acid and ursodeoxycholic acid as pharmacotherapies for drug-induced liver injury.²⁶ The clinical courses of patients with ALT elevation during the risk period were further described.

Statistical analysis

Patient characteristics at the start of the observation period were summarized using descriptive statistics, including demographics, MTX use, and ALT elevation 90 days prior to the observation period. Continuous variables are described as the median and interquartile range (IQR), while categorical variables are described as the number of patients and percentages. The analysis included hospital-based patients with rare disease who had both MTX prescriptions and ALT levels >3 × ULN. Age-adjusted incidence rate ratio (aIRR) and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, in which the ALT elevation risk during the risk and baseline periods was compared and adjusted for age.²¹ A separate analysis was conducted to assess ALT ⩾5 × ULN and examine more severe hepatotoxicity. The aIRR was calculated per calendar month to account for temporal changes in the cumulative number of patients.

Sensitivity analyses were conducted to assess the robustness of the study findings. To confirm the effects by patient background, the aIRR stratified patients by (i) age and (ii) sex. In addition, analyses were conducted (iii) excluding patients with MTX prescription, (iv) excluding patients with ALT elevation 90 days prior to the start of observation, and (v) excluding patients who received MTX injection between the start of observation and initial ALT elevation. To validate the definitions of the observation and risk periods, sensitivity analyses were performed by (vi) defining the observation period from the start of the diagnosis of the target diseases to 180 days following the diagnosis of the target diseases and (vii) defining the risk period from the start of MTX treatment to the final dose.

Given that MTX-treated patients frequently receive concomitant medications, an additional analysis was conducted to assess ALT elevation among patients not exposed to high-risk hepatotoxic drugs. Drugs classified under LiverTox categories A and B, which include agents associated with liver injury, were identified from the LiverTox database (https://www.ncbi.nlm.nih.gov/books/).²⁷ The aIRR was estimated for patients who did not receive concomitant medications categorized under LiverTox A or B from the time of diagnosis until ALT elevation. Patients with liver diseases commonly show ALT elevation and must therefore undergo careful monitoring of liver function during MTX treatment. Therefore, in this study, sensitivity analyses were conducted, excluding patients with a diagnosis of hepatitis type B and/or type C and patients with comorbid liver diseases during the observation period.

According to the policy on database utilization, patients involving ⩽2 participants were not reported with their numbers. All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA) and TIBCO Spotfire Desktop version 11.4.0 (TIBCO Spotfire, Inc., Palo Alto, CA, USA).

The reporting of this study conforms to the REporting of Studies Conducted using Observational Routinely Collected Health Data for Pharmacoepidemiology statement (RECORD-PE) statement.²⁸

Results

Patient characteristics

The flowchart of patient selection is presented in Figure 2. A total of 1,316,572 patients were included in the P-MICS database between April 2016 and March 2024. Among them, 3477 patients received a confirmed diagnosis of the target diseases at hospitals, and 587 patients were prescribed MTX during the observation period (571 (29%) of 1950 with JIA, 26 (2%) of 1341 with IBD, and 16 (5%) of 299 with psoriasis). In addition, 81 patients developed ALT elevation >3 × ULN. The number of diagnosed patients was 72 for JIA, 14 for IBD, and fewer than 2 for psoriasis. In addition, six patients had both JIA and IBD.

Figure 2.

Flow chart of the study population.

Table 1 summarizes patient demographic characteristics and liver function test results on the day of ALT elevation. The median age of patients with ALT levels three or more times higher than normal was 7 years (IQR 4–11), and the majority of patients were female (53%) and had JIA (89%). Their median plasma ALT, AST, TB, and gamma-glutamyl transpeptidase (GGT) levels at the start of the observation period were 19 U/L, 27 U/L, 0.4 mg/dL, and 22.5 U/L, respectively. Liver function levels were within normal ranges, indicating the absence of baseline liver dysfunction. MTX was prescribed for 27 patients, and 23 patients had ALT elevation prior to the observation period. Among the 81 patients, 21 patients developed ALT elevation prior to MTX administration. The remaining 60 patients were prescribed MTX between the start of observation and the initial ALT elevation, receiving four doses (IQR 1–6).

Table 1.

Patient characteristics.

	All (n = 81)
Age, years, median (IQR)	7 (4–11)
Sex
Male	38 (47%)
Female	43 (53%)
Target diseases, n (%)
JIA	72 (89%)
IBD	14 (17%)
Psoriasis	⩽2 (⩽2%)
Laboratory parameters, median (IQR)
ALT, U/L	19 (12–39)
AST, U/L	27 (20–41)
TB, mg/dL	0.4 (0.3–0.6)
GGT, U/L	22.5 (13–37.3)
MTX use, n (%)^a	27 (33%)
ALT elevation, n (%)^a	23 (28%)

Laboratory parameters represent the highest serum values recorded in the most recent observation period.

Cases with ALT >3 × ULN prior to the observation period.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; IBD, inflammatory bowel disease; IQR, interquartile range; JIA, juvenile idiopathic arthritis; MTX, methotrexate; TB, total bilirubin; ULN, upper limit of normal.

SCCS analysis reveals increased risk of ALT elevation with MTX treatment

A total of 45 patients (56%) experienced ALT elevation during the risk period, whereas the remaining 36 developed ALT elevation during the baseline period. The risk of ALT elevation was significantly increased during MTX treatment (aIRR: 2.27 (95% CI: 1.45–3.55) and crude IRR: 2.26 (95% CI: 1.44–3.54); Table 2). The aIRRs for JIA and IBD were 2.60 (95% CI: 1.61–4.19) and 1.90 (95% CI: 0.58–6.23), respectively. However, we could not calculate the aIRR for patients with psoriasis owing to the small sample size. Details of the characteristics of the subgroup that developed ALT elevation during the risk period are shown in Supplemental Table 3.

Table 2.

Age-adjusted incidence rates of abnormal ALT elevation associated with MTX administration.

	Cases, n (%)	Cases with outcomes during the risk period (n)	Risk period (person-years)	Cases with outcomes during the baseline period (n)	Baseline period (person-years)	Age-adjusted incidence rate ratio (95% CI)
All	81 (100)	45	27.7	36	50.1	2.27 (1.45–3.55)
JIA	72 (89)	43	27.0	29	47.2	2.60 (1.61–4.19)
IBD	14 (17)	6	2.1	8	5.2	1.90 (0.58–6.23)

The number of patients with psoriasis was insufficient to reach the required sample size for the self-controlled case series analysis.

ALT, alanine aminotransferase; CI, confidence interval; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; MTX, methotrexate.

Sensitivity analysis revealed no significant differences from the results (Supplemental Table 4). In the calendar month analysis, the number of patients increased, and the aIRR and 95% CI became narrower and more stable over time (Supplemental Figure 1). When ALT elevation was defined as ⩾5 × ULN, the aIRR remained consistent with the results at 2.11 (95% CI: 1.20–3.73).

Clinical course of patients with ALT elevation during the risk period

The clinical course following initial ALT elevation was further examined to assess liver injury severity (Table 3). Among the 45 patients with ALT elevation during the risk period selected for this analysis to illustrate the clinical course and management following liver injury, some received folic acid (n = 20), glycyrrhizic acid (n = 5), and ursodeoxycholic acid (n = 4). The 44 patients (98%) were re-prescribed MTX after ALT elevation, while the remaining patient had no further medical data available.

Table 3.

Clinical course and management of liver injury following abnormal ALT elevation.

	All (n = 45)	Folic acid (n = 20)	Glycyrrhizic acid (n = 5)	Ursodeoxycholic acid (n = 4)
MTX re-prescription, n	44	19	5	4
ALT normalization, n^a	35	14	4	3
Days to ALT normalization, median (IQR)	32 (17–63)	27 (19–49)	17 (12–33)	18 (13–25)
Relapse of ALT elevation, n^b	11	0	⩽2	3
Diagnosis of liver failure, n	0	0	0	0

Cases include patients who developed abnormal ALT elevation during the risk period, in whom the liver function was monitored, and management interventions following initial ALT elevation were initiated.

ALT levels were below the upper limit of normal after the initial abnormal ALT elevation.

ALT levels exceeded three times the upper limit of normal after the first normalization of ALT levels.

ALT, alanine aminotransferase; IQR, interquartile range; MTX, methotrexate.

Overall, 35 patients (78%) achieved ALT normalization within a median period of 32 days (IQR 17–63). None of the patients were diagnosed with liver failure following ALT elevation. Among this population, the ALT normalization rates were 70%, 80%, and 75% within a median period of 27 days (IQR 19–49), 17 days (IQR 12–33), and 18 days (IQR 13–25) among those who received folic acid, glycyrrhizic acid, and ursodeoxycholic acid, respectively. The time to ALT normalization was shorter among patients who received hepatoprotective medications than among those who received non-pharmacologic management.

Among the 35 patients who were re-prescribed MTX and achieved ALT normalization, 11 experienced a relapse of ALT elevation. However, TB levels were assessed in 38 patients, and 7 patients developed TB elevation. However, none of the patients in the folic acid group experienced TB elevation.

Discussion

Our findings suggested that most patients in our cohort were diagnosed with JIA, and the incidence of ALT elevation during MTX treatment was approximately twice as high as that during the non-treatment period, suggesting an increased risk of ALT elevation during MTX administration. The clinical course analysis indicated that the likelihood of severe liver failure following MTX administration may be low, consistent with findings in adults.^6,11 Our SCCS analysis demonstrated that MTX use elevates liver enzymes in those with pediatric inflammatory diseases. Most of the study participants were patients with JIA, and our results regarding the association with MTX and elevated ALT are consistent with prior studies on JIA.^12,13 In the treatment of rheumatoid disorders, discontinuation or dose adjustment of MTX is recommended in patients with ALT greater than three times normal ULN levels, as MTX-induced liver injury can compromise treatment continuity.²⁹ These results emphasize the need for routine liver function monitoring, including ALT level assessment, to facilitate early detection and management of MTX-induced liver injury in pediatric patients. Risk factors for ALT elevation following MTX treatment could not be identified in our analysis. Further analysis is required to clarify the factors associated with MTX-induced liver injury in children.

Several management strategies have been proposed for MTX-induced liver injury. In this study, the use of folic acid, glycyrrhizic acid, and ursodeoxycholic acid was examined. Folic acid supplementation is common and is currently the recommended medical management strategy to manage side effects.^3,6,29 Furthermore, glycyrrhizic acid and ursodeoxycholic acid are commonly used as hepatoprotective agents in Japan. Folic acid supplementation restores intracellular folate levels and prevents liver dysfunction in adults with rheumatoid arthritis receiving MTX treatment,³⁰ and is recommended to mitigate MTX-associated toxicity.³ Our findings indicate that folic acid supplementation may prevent the exacerbation of MTX-induced liver dysfunction, including the relapse of elevated liver enzymes and elevated TB in pediatric patients with inflammatory disease. Folic acid does not appear to be beneficial for the repair of liver inflammation and may affect the toxicity of MTX. Further research could focus on an in-depth analysis of this point. These results highlight the need for early detection and intervention to mitigate liver injury risk and optimize patient outcomes, particularly in children with JIA.

The assessment of drug safety in rare diseases is usually constrained by the limited number of samples.³¹ SCCS design was employed to minimize biases associated with inter-individual comparisons, providing valid results even with a small sample size. As P-MICS data were derived from Japanese pediatric hospitals, these results may be generalizable to pediatric patients receiving MTX treatment in similar healthcare settings. Sensitivity analyses helped address potential confounding factors related to MTX-treated patient status, demonstrating the robustness of these findings. Genetic factors, including methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms that influence MTX metabolism, have been associated with an increased risk of MTX-induced liver injury.^32,33 A self-controlled design offers a methodologically sound approach to automatically control for genetic confounders and assess drug safety in rare diseases. Therefore, the ability of self-controlled designs using electronic health record databases to analyze individual cases makes them a valuable tool for pharmacovigilance research in rare diseases. Given the limited safety data available for pediatric rare diseases, these findings provide essential insights into safe and appropriate drug use in pediatric clinical practice. Further research is required to refine risk management strategies for medications used in this vulnerable population. Identifying both potential risks and benefits will ensure that pediatric patients with rare diseases receive safe and effective treatment tailored to their clinical needs.

Limitations

This study has some limitations. Follow-up was restricted to patients who remained within the same medical institution, whereas those transferred to other hospitals could not be tracked. The participants were patients with rare diseases, and most received follow-up care and treatment at the same hospital following the initial diagnosis. Therefore, they are likely to represent the target study population, thereby mitigating this limitation. In addition, hospitalized patients may present with acute symptoms requiring intensive monitoring, which may limit the generalizability of these findings. Further studies with larger sample sizes are necessary to confirm these results and improve their applicability. Finally, medication was administered based on prescription records, which may have overestimated actual drug use in some cases.

Conclusion

In conclusion, our SCCS analysis demonstrated an increased risk of abnormal ALT elevation during MTX treatment in pediatric patients with rare inflammatory diseases. These findings emphasize the importance of liver function monitoring and appropriate pharmacotherapy to prevent the exacerbation of liver dysfunction in pediatric patients receiving MTX therapy. In addition, the self-controlled study design used in this study offers a valuable pharmacovigilance approach for assessing drug safety in rare diseases. The analysis of individual clinical courses also suggests that folic acid supplementation may serve as a potential strategy to prevent the exacerbation of MTX-induced liver injury. However, further research is needed, given the small sample size.

Supplemental Material

sj-docx-1-taw-10.1177_20420986251392451 – Supplemental material for Methotrexate use and risk of abnormal alanine aminotransferase elevation in children with rare inflammatory diseases: a self-controlled case series analysis using a pediatric electronic health record database in Japan

Supplemental material, sj-docx-1-taw-10.1177_20420986251392451 for Methotrexate use and risk of abnormal alanine aminotransferase elevation in children with rare inflammatory diseases: a self-controlled case series analysis using a pediatric electronic health record database in Japan by Masayoshi Nakakuni, Azusa Hara, Kosuke Nakano, Seiji Mitsui, Naoko Deguchi and Seiko Miyazaki in Therapeutic Advances in Drug Safety

Supplemental Material

sj-docx-2-taw-10.1177_20420986251392451 – Supplemental material for Methotrexate use and risk of abnormal alanine aminotransferase elevation in children with rare inflammatory diseases: a self-controlled case series analysis using a pediatric electronic health record database in Japan

Supplemental material, sj-docx-2-taw-10.1177_20420986251392451 for Methotrexate use and risk of abnormal alanine aminotransferase elevation in children with rare inflammatory diseases: a self-controlled case series analysis using a pediatric electronic health record database in Japan by Masayoshi Nakakuni, Azusa Hara, Kosuke Nakano, Seiji Mitsui, Naoko Deguchi and Seiko Miyazaki in Therapeutic Advances in Drug Safety

Footnotes

Acknowledgements

We thank the collaborating medical institutions of P-MICS (); all study participants for their contributions; Professor Masaaki Mori (Institute of Science, Tokyo Hospital) for valuable advice on clinical practice for JIA; Shinji Kobayashi, Yutaka Ohnuki, and Shingo Sekine (Nature Insight Co., Ltd.) for their support with statistical analysis and data mining; Life Science Computing Co., Ltd. for assistance with data collection system maintenance; and H&H Connect Co., Ltd. for assistance with data management. We also thank Editage for editorial support.

Declarations

ORCID iDs

Masayoshi Nakakuni

Azusa Hara

Seiko Miyazaki

Supplemental material

Supplemental material for this article is available online.

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