Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study

Abstract

Background:

Methotrexate is central to the management of rheumatoid arthritis (RA). However, its use is often limited by methotrexate intolerance.

Objectives:

This study aims to explore the association between alternative methotrexate dosing methods and methotrexate intolerance.

Design:

A cross-sectional study.

Methods:

A cross-sectional survey was conducted on patients with RA receiving methotrexate for at least 3 months at the outpatient clinic of King Saud University Medical City, Riyadh, Saudi Arabia. The electronic survey collected data on demographics, marital and educational status, methotrexate use, Methotrexate Intolerance Severity Score (MISS), and Health Assessment Questionnaire. Statistical analyses (univariate and linear or logistic regression) were conducted to evaluate the associations between the administration methods and methotrexate intolerance (MISS ⩾6).

Results:

The study included 154 patients, predominantly female (89%; mean age (standard deviation, ±SD): 50 (±12) years). Methotrexate tolerance was observed in 64% of the participants, while 36% had a MISS above the cutoff point of 6, indicating intolerance. Methotrexate-intolerant patients were younger (mean age (±SD): 47 (±12) years) than tolerant patients (mean age (±SD): 54 (±12) years; p = 0.005). No significant differences were found between methotrexate-tolerant and methotrexate-intolerant patients regarding dose, frequency, relation to meals, and time of day.

Conclusion:

Methotrexate tolerance was not associated with different administration methods: split-dose versus single weekly dose, or subcutaneous versus oral administration.

Plain language summary

Methotrexate use and intolerance in patients with rheumatoid arthritis

Methotrexate is one of the most important medications for the control of rheumatoid arthritis, but its use is associated with side effects. In this study, we looked at whether changing the method of using methotrexate as a subcutaneous administration or split oral dose may reduce the side effects. We did this study by sending a survey asking questions on methotrexate intolerance to RA patients attending rheumatology clinics at King Saud University Medical City, Riyadh, Saudi Arabia. As a result, 154 patients answered the survey, and we analyzed the information to find that methotrexate intolerance was not associated with different administration methods.

Keywords

methotrexate intolerance rheumatoid arthritis route of administration split dose subcutaneous

Introduction

Methotrexate (MTX) is an antifolate drug that is widely recommended for the management of rheumatoid arthritis (RA).¹ Since its discovery as a therapeutic agent for rheumatic diseases, it has remained one of the gold standards for RA management.^1,2 However, its use is often compromised by adverse drug reactions, particularly MTX intolerance.^3–5 Owing to the significant impact of MTX intolerance, the recent 2021 guidelines issued by the American College of Rheumatology (ACR) recommend various MTX dosing strategies, including route and frequency adjustments, to preserve MTX as an essential treatment option for patients with RA.⁶ MTX intolerance is associated with dosage, oral administration, and folic acid supplementation.⁷ To mitigate MTX intolerance, approaches such as shifting to subcutaneous administration, splitting the dose, or increasing folic acid therapy may be considered.^8–10

Although the mechanism of action of MTX is well documented, some aspects of its effects remain unclear.¹¹ The side effects, particularly methotrexate intolerance, are understood to result from mechanisms such as its accumulation in sensitive epithelial cells, binding to the central nervous system, and stimulation by emetic agents, all of which contribute to its gastrointestinal side effect profile.¹² This explains the physiological component of intolerance; however, much remains to be explored regarding the behavioral, anticipatory, or associative aspects. Interestingly, low responsiveness to MTX has been found to be related to psychological factors such as depression and anxiety, underscoring the importance of addressing the psychological domains of MTX intolerance.¹³ MTX intolerance, including behavioral symptoms, is influenced by gender and is more closely associated with females.¹⁴ However, the influence of MTX administration on behavioral and psychological domains has yet to be explored. Given the limited available information, this study aimed to explore the association between alternative methotrexate dosing methods (single weekly vs split and oral vs subcutaneous) and methotrexate intolerance. This study also focuses particularly on understanding the psychological aspects of MTX intolerance in the context of recent recommendations for split dosing and subcutaneous administration.

Methods

Study design and setting

This cross-sectional, survey-based study was observational in nature, and its reporting conformed to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE).¹⁵ Recruitment was conducted at the rheumatology outpatient clinic of King Saud University Medical City, Riyadh, Saudi Arabia.

Participants and recruitment

Participants were recruited from the adult rheumatology outpatient clinic’s waiting area (conveniently). Participants were approached and invited to participate, and consent was obtained after confirming that they had a diagnosis of RA and had been receiving MTX therapy for at least 3 months (inclusion criteria). Children or participants who were mentally incapable of answering the survey questions were excluded. The participants were provided with a tablet computer with a survey link to complete the questionnaire. A member of the research team was always available to assist with any questions or provide clarification. Recruitment began at the end of 2021 and continued until January 2024.

Variables and data source

Data were collected using a structured Google Form designed for this study. The form included an information sheet on the research with electronic consent, participant demographics (age, sex, socioeconomic status, education, and smoking status), medical history, and methotrexate-related information. The methotrexate-related data collected included the dosing regimen (single weekly dose or split weekly dose), route of administration (oral or subcutaneous), and timing of dose in relation to the time of day (AM or PM) and meals (before or after meals). Split-dose MTX could be either a weekly dose split over 2–3 days or a single-day dose separated by at least 8 h.^9,16 Additional information included the dose and frequency of folic acid supplementation.

Measurements

Two translated and validated tools were used. The first was the Methotrexate Intolerance Severity Score (MISS),⁴ which was developed in 2011 and translated and validated in Arabic in 2019.³ This tool consists of 12 items, with patients rating each item on a severity scale ranging from 0 to 3. The survey assesses MTX intolerance, covering four aspects: stomach aches, nausea, vomiting, and behavioral complaints. The total score was computed, with a cutoff point of <6 indicating tolerance to MTX. Higher scores (⩾6) suggested that the patient was experiencing MTX intolerance, which was used as the definition of intolerance. MTX intolerance can be divided into anticipatory (before MTX), associative (when thinking of MTX), and behavioral (restlessness, irritability, crying, and refusal to take MTX in response to its gastrointestinal side effects).¹⁷ The second tool used to assess disease severity as reflected by disability was the Health Assessment Questionnaire (HAQ).¹⁸ Originally developed in 1982, the HAQ was translated into Arabic and validated in 2003.^19,20 The questionnaire included multiple sections assessing the patients’ daily activities in terms of difficulty on a scale of 0–3. Patients were also asked whether they required assistance or devices for daily activities, and rated their pain and the overall impact of RA on their lives on a visual analog scale of 0–10, including whether they experienced morning stiffness. The computed scores categorized the patients into three subgroups: mild (0–1.000), moderate (1.250–2.000), and severe (>2.000).

Publication bias

Not applicable; the study is observational, and participants were included by convenient sampling.

Study size

In a very similar study, the difference in achieving low disease activity between patients receiving single dose versus split dose was 13%; thus, using a sample size calculator (caluculator.net), a sample size of 174 or more measurements/surveys is needed to have 95% confidence that the real value is within ±5% of the measured/surveyed value.⁹

Statistical methods

Data were exported from Google Forms, coded, and entered into Statistical Package for the Social Sciences (SPSS) version 28.²¹ Categorical data were presented as numbers and percentages, whereas continuous data were expressed as mean with standard deviation (SD) or median with interquartile range (IQR), as appropriate. Differences between groups were assessed using the Chi-square test, independent samples t test, or Mann–Whitney U test, depending on the data distribution. Both binary logistic and linear regression models were used to predict outcomes, adjusting for confounders that were significantly different in the univariate analysis (between the tolerant and intolerant patient groups). To categorize the anticipatory, associative, and behavioral domains of the MISS, a score of ⩾1 in the question or domain is considered a yes. Missing data handling was not required as no data were missing.

Results

In total, 154 patients were recruited for this study. The majority were tolerant to MTX, with the following characteristics: predominantly female (89%), with a mean (±SD) age of 50 (±12) years, 50 years or more (57%), residing in Riyadh (77%), married (74%), predominantly retired (70%), and possessing graduate-level education (42%). The majority had comorbidities (64%), were less likely to be smokers, experienced morning stiffness, reported intermediate pain with a median (IQR) of 50 (50–60), had a median arthritis impact score of 50 (50–60), and had a moderate disability score of 1.125 (1.000–1.500). The MISS equal to or exceeded the cutoff point of 6 in only 36% of participants. To further explore potential confounders, the participants were stratified into MTX-tolerant and MTX-intolerant groups. Demographic characteristics were generally similar between the two groups, except for differences in age, marital status, pain levels, and prevalence of morning stiffness. The MTX-intolerant group was younger, with a mean age of 47 (±12) years compared with 54 (±12) years in the tolerant group (p = 0.005). Supplemental Figures 1 and 2 shows the relationship between age, dose and MTX-intolerance with older group being more tolerant to higher doses. In addition, MTX-intolerant participants were less likely to be married than MTX-tolerant participants (61% vs 78%; p = 0.041). The intolerant group also reported greater pain, with a median score of 60, and a higher prevalence of morning stiffness (75%) than the tolerant group (median pain score, 50; morning stiffness, 57%; p = 0.037) (Table 1).

Table 1.

Demographics, disease information, and disability stratified by methotrexate intolerance score.

Item	Total, N = 154	Tolerant (<6), N = 98	Intolerant (⩾6), N = 56	p-Value
Gender, N (%)
Male	17 (11.0)	13 (13.3)	4 (7.1)	0.295
Female	137 (89.0)	85 (86.7)	52 (92.9)
Age (years), mean (SD)	50 (12)	54 (12)	47 (12)	0.005*
Age, years, N (%)
Less than 55	66 (43)	34 (34)	32 (57)	0.007*
50 or more	89 (57)	65 (66)	24 (43)
Living, N (%)
Outside Riyadh	36 (23.4)	24 (24.5)	12 (21.4)	0.698
Riyadh	118 (76.6)	74 (75.5)	44 (78.6)
Marital status, N (%)
Married	110 (71.4)	76 (77.6)	34 (60.7)	0.041*
Smoking, N (%)
Yes	6 (3.9)	2 (2.0)	4 (7.1)	0.190
Employment, N (%)
None/Retired	107 (69.5)	73 (74.5)	34 (60.7)	0.105
Government	7 (4.5)	4 (4.1)	3 (5.4)
Private	6 (3.9)	5 (5.1)	1 (1.8)
Other	34 (22.1)	16 (16.3)	18 (32.1)
Educational level, N (%)
No education	26 (16.9)	17 (17.3)	9 (16.1)	0.502
Undergraduate	56 (36.4)	39 (39.8)	17 (30.4)
Graduate	65 (42.2)	37 (37.8)	28 (50.0)
Postgraduate	7 (4.5)	5 (5.1)	2 (3.6)
Comorbidities,^a N (%)
Yes	99 (64.3)	63 (64.3)	36 (64.3)	1.000
Disease duration (years), mean (SD)	12 (9)	12 (10)	11 (9)	0.306
Pain (score), median (IQR)	50 (50–60)	50 (50–70)	60 (50–70)	0.049*
Impact of arthritis (score), median (IQR)	50 (50–60)	50 (50–70)	60 (60–80)	0.301
Morning stiffness, N (%)
Yes	97 (63.4)	56 (57.1)	41 (74.5)	0.037*
Health assessment questionnaire (score), median (IQR)	1.125 (1.000–1.500)	1.063 (0.625–1.375)	1.313 (1.000–1.625)	0.600

Hypertension, diabetes, dyslipidemia, or any other chronic condition.

Significance was set at p < 0.050.

IQR, interquartile range; SD, standard deviation.

Regarding MTX-related information, most participants received MTX as a single dose (86%), with a mean (±SD) dose of 14 (±5) mg. The majority received the drug orally (78%) for an average of 8 (±7) years, taking it in the evening (73%) and after meals (72%), with folic acid supplementation at a mean dose of 10 (±5) mg. No significant differences were observed between the MTX-tolerant and MTX-intolerant groups (Table 2). When exploring specific items of MTX intolerance, more than half of the participants reported behavioral symptoms (58%), and nearly half experienced stomach (upper abdominal) pain after taking the dose (48%). Other symptoms, including associative symptoms (occurring when thinking about methotrexate) and anticipatory symptoms (before taking methotrexate), were less common in the overall population. Even when MTX intolerance items were stratified based on single versus split doses or oral versus subcutaneous routes, no significant differences were observed (Tables 3 and 4). Binary logistic and linear regression analyses were performed to assess the odds of experiencing intolerance symptoms after adjusting for confounders such as age and pain. Marital status was excluded from the regression model to avoid multicollinearity, as it was related to age, and pain was associated with morning stiffness. After adjustment, no significant odds ratios or beta coefficients were found for split versus single dosing or the oral versus subcutaneous route. The beta coefficients for MISS anticipatory items in the split-dose group ranged from 0.571 for Stomach ache (95% confidence interval (CI): 0.175–1.857; p = 0.352) to vomiting 3.189 (95% CI: 0.553–18.378; p = 0.194) in Table 3, and for the subcutaneous route from 0.565 (95% CI: 0.064–5.013; p = 0.608) in vomiting to 1.439 (95% CI: 0.623–3.323; p = 0.349) in Table 4. Finally, radar charts were used to visualize MTX intolerance in relation to single versus split dosing and oral versus subcutaneous administration. The radar chart (Figure 1(a)) indicated that patients receiving split dosing were less likely to cry or refuse to take methotrexate. In contrast, subcutaneous administration showed better outcomes than oral administration, particularly with respect to vomiting after administration (Figure 1(b)). Additionally, Figure 1(c) demonstrates that the subcutaneous route had the lowest levels of MTX intolerance according to the MISS items. Moreover, Figure 2 highlights the differences between split dosing and subcutaneous administration, particularly in behavioral symptoms, that is, cries when taking MTX (higher with split dosing at 53%) and anticipatory symptoms (higher with the subcutaneous route at 31%).

Table 2.

Methotrexate-related information stratified by methotrexate intolerance score.

Item	Total, N = 154	Tolerant (<6), N = 98	Intolerant (⩾6), N = 56	p-Value
Split dose, N (%)
Yes	21 (13.7)	13 (13.3)	8 (14.5)	0.811
Weekly dose of methotrexate (mg), mean and SD	13.8 (5.4)	13.4 (5.7)	14.3 (4.8)	0.331
Dosage form, N (%)
Oral	120 (77.9)	79 (80.6)	41 (73.2)	0.316
Subcutaneous	34 (22.1)	19 (19.4)	15 (26.8)
Duration of methotrexate use (years), mean and SD	8 (7)	7 (6)	8 (7)	0.349
Time of dose during the day
AM	42 (27.3)	26 (26.5)	16 (28.6)	0.851
PM	112 (72.7)	72 (73.5)	40 (71.4)
Methotrexate dose in relation to meal
Before meal	10 (6.5)	4 (4.1)	6 (10.7)	0.095
After meal	111 (72.1)	76 (77.6)	35 (62.5)
Between meals	33 (21.4)	18 (18.4)	15 (26.8)
Weekly folic acid dose (mg), mean and SD	10 (5)	9 (6)	10 (5)	0.831

AM, morning; PM, evening; SD, standard deviation.

Table 3.

MTX intolerance symptoms and use of weekly split dose.

Item	Total, N = 154	Split, N = 21	Single, N = 133	p Value	Regression (beta or adjusted odds ratio,^a 95% CI, p-Value)
Total MISS, median, and IQR	3 (2–5)	3 (1–11)	3 (2–5)	0.714	0.133 (−2.971, 3.238), 0.933
Stomach ache (pain) after MTX, N (%)	73 (47.7)	10 (47.6)	63 (47.7)	1.000	0.962 (0.379, 2.440), 0.934
Nausea after MTX, N (%)	65 (42.5)	9 (42.9)	56 (42.4)	1.000	1.012 (0.380, 2.700), 0.980
Vomiting after taking MTX, N (%)	20 (13.1)	4 (19.0)	16 (12.1)	0.482	1.944 (0.556, 6.793), 0.298
Anticipatory
Stomach ache (pain) several hours to 1 day before MTX, N (%)	42 (27.5)	4 (19.0)	38 (28.8)	0.438	0.571 (0.175, 1.857), 0.352
Nausea several hours to 1 day before MTX, N (%)	32 (20.9)	5 (23.8)	27 (20.5)	0.774	1.335 (0.419, 4.257), 0.625
Vomiting hours to 1 day before taking MTX, N (%)	7 (4.6)	2 (9.5)	5 (3.8)	0.246	3.189 (0.553, 18.378), 0.194
Associative
Stomach ache (pain) when thinking of MTX, N (%)	39 (25.5)	7 (33.3)	32 (24.2)	0.421	1.665 (0.586, 4.735), 0.339
Nausea when thinking of MTX, N (%)	38 (24.8)	6 (28.6)	32 (24.2)	0.786	1.413 (0.486, 4.106), 0.525
Behavioral
Restless when taking MTX, N (%)	60 (39.2)	8 (38.1)	52 (39.4)	1.000	0.935 (0.351, 2.491), 0.893
Irritable when taking MTX, N (%)	41 (26.8)	7 (33.3)	34 (25.8)	0.441	1.346 (0.486, 3.728), 0.567
Refuses to take MTX, N (%)	60 (39.2)	9 (42.9)	51 (38.6)	0.811	1.218 (0.473, 3.139), 0.683
Cries when taking MTX, N (%)	27 (17.6)	2 (9.5)	25 (18.9)	0.372	0.441 (0.094, 2.063), 0.299
Total anticipatory, N (%)	55 (35.7)	6 (28.6)	48 (36.4)	0.625	0.696 (0.243, 1.988), 0.498
Total associative, N (%)	48 (31.2)	8 (38.1)	40 (30.3)	0.460	1.566 (0.573, 4.275), 0.382
Total behavioral, N (%)	89 (57.8)	16 (76.2)	72 (54.5)	0.095	2.772 (0.943, 8.153), 0.064

Adjusted for age and pain.

CI, confidence interval; IQR, interquartile range; MISS, Methotrexate Intolerance Severity Score; MTX, methotrexate.

Bold: Indicating total value.

Table 4.

MTX intolerance symptoms and MTX dosage forms.

Item	Total, N = 154	Subcutaneous, N = 34	Oral, N = 120	p Value	Regression (beta or adjusted odds ratio,^a 95% CI, p-value)
Total MISS, median, and IQR	3 (2–5)	5 (1–13)	3 (2–5)	0.604	1.408 (−1.176, 3.992), 0.284
Stomach pain after MTX, N (%)	74 (48.1)	15 (44.1)	59 (49.2)	0.698	0.769 (0.351, 1.682), 0.510
Nausea after MTX, N (%)	66 (42.9)	17 (50.0)	49 (40.8)	0.433	1.203 (0.538, 2.689), 0.653
Vomiting after taking MTX, N (%)	20 (13.0)	3 (8.8)	17 (14.2)	0.568	0.492 (0.128, 1.888), 0.301
Anticipatory
Stomach pain several hours to 1 day before MTX, N (%)	43 (27.9)	12 (35.3)	31 (25.8)	0.286	1.439 (0.623, 3.323), 0.394
Nausea several hours to 1 day before MTX, N (%)	32 (20.8)	9 (26.5)	23 (19.2)	0.348	1.280 (0.496, 3.303), 0.610
Vomiting hours to 1 day before taking MTX, N (%)	7 (4.5)	1 (2.9)	6 (5.0)	1.000	0.565 (0.064, 5.013), 0.608
Associative
Stomach pain when thinking of MTX, N (%)	39 (25.3)	12 (35.3)	27 (22.5)	0.179	1.636 (0.687, 3.896), 0.267
Nausea when thinking of MTX, N %	38 (24.7)	10 (29.4)	28 (23.3)	0.502	1.280 (0.528, 3.100), 0.585
Behavioral
Restless when taking MTX, N (%)	61 (39.6)	18 (52.9)	43 (35.8)	0.078	1.839 (0.836, 4.048), 0.130
Irritable when taking MTX, N (%)	41 (26.6)	10 (29.4)	31 (25.8)	0.666	1.014 (0.426, 2.416), 0.974
Refuses to take MTX, N (%)	60 (39.0)	15 (44.1)	45 (37.5)	0.552	1.212 (0.551, 2.664), 0.633
Cries when taking MTX, N (%)	27 (17.5)	9 (26.5)	18 (15.0)	0.131	1.800 (0.708, 4.576), 0.217
Total anticipatory, N (%)	55 (35.7)	15 (44.1)	40 (33.3)	0.311	0.831 (0.379, 1.821), 0.644
Total associative, N (%)	48 (31.2)	14 (41.2)	34 (28.3)	0.208	1.413 (0.631, 3.162), 0.400
Total behavioral, N (%)	89 (57.8)	19 (55.9)	70 (58.3)	0.845	1.605 (0.702, 3.670), 0.262

Adjusted for age and pain

CI, confidence interval; IQR, interquartile range; MISS, Methotrexate Intolerance Severity Score; MTX, methotrexate.

Bold: Indicating total value.

Figure 1.

(a) Average methotrexate intolerance score according to single versus split weekly dosing. (b) Average methotrexate intolerance score according to oral versus subcutaneous route of administration. (c) Average methotrexate intolerance score according to single and split dosing, and subcutaneous route of administration.

Figure 2.

Level of methotrexate intolerance in different dosage forms and frequency.

Discussion

Most participants in this study were female, married, educated, and demonstrated a general tolerance to methotrexate. Despite this, the participants reported experiencing varying degrees of pain, morning stiffness, and moderate disability. Notably, patients who were intolerant of MTX tended to be younger, less likely to be married and exhibited greater pain and a higher prevalence of morning stiffness. The most pronounced domain of MTX intolerance observed in this study was behavioral symptoms, followed by stomachaches after dose administration. The radar charts highlight a slight advantage of the subcutaneous route over other methods in some aspects. In addition, a clear difference was observed between split doses and the subcutaneous route in terms of behavioral and anticipatory symptoms. While this study did not conclusively demonstrate that split doses or the subcutaneous route are superior to single weekly or oral doses in reducing MTX intolerance, the findings are still valuable for contributing to the body of evidence regarding optimal RA management. The results suggest a potential benefit of the subcutaneous route but no clear advantage for the split-dose approach. The 2021 ACR guidelines for the management of RA conditionally recommend MTX over other therapeutic options, highlighting its importance in treatment algorithms.⁶ Although oral MTX is preferred over subcutaneous administration despite evidence suggesting the superiority of the subcutaneous route,²² this preference may be due to factors unrelated to MTX intolerance, such as ease of administration. Our findings support this view, as no significant benefit of the subcutaneous route over oral administration in terms of intolerance was observed. Furthermore, evidence supporting the split-dose approach in the guidelines carries some degree of uncertainty.⁹ This study does not suggest a lack of benefit of split dosing or subcutaneous administration in alleviating MTX intolerance; however, it is important to acknowledge the limitations of this study. Interestingly, the differences in MTX intolerance symptoms between split and single doses suggested that patients receiving split doses were less likely to cry or refuse therapy. The psychological impact of MTX is underexplored despite its known effects on multiple receptors in the central nervous system.¹² The exact reasons for the anticipatory, associative, and behavioral symptoms of MTX remain unclear, although depression and anxiety have been identified as predictors of a poor response.¹³ The higher anticipatory symptoms observed in the subcutaneous route group may indicate injection-related anxiety.²³

Limitations

First, the cross-sectional nature of the study prevented the establishment of causality, emphasizing the need for longitudinal studies. In addition, patients included in either the split-dose or subcutaneous groups may have already had a high baseline level of MTX intolerance, and the small sample size could have limited the detection of significant differences. Recruiting patients who had been on a stable MTX dose and management regimen for at least 3 months contributed to the low number of participants and the extended recruitment period. Both MTX intolerance and MTX toxicity may be influenced by various factors such as renal or liver function; lack of laboratory data may prevent the detection of important confounders. The dynamic nature of RA management, particularly in younger patients, further complicates studies on MTX intolerance.

Conclusion and relevance

In conclusion, although we did not detect a difference in methotrexate intolerance between split and single weekly doses nor between oral and subcutaneous administration, further research is needed to identify strategies to minimize MTX intolerance, as methotrexate remains a cornerstone in the management of RA. Much remains unknown about MTX, and understanding needs to be strengthened by accumulating evidence from both observational and experimental study designs. This signifies the importance of this study and encourages researchers to conduct further research exploring the effects of MTX on patients from different perspectives.

Supplemental Material

sj-doc-1-taw-10.1177_20420986251349449 – Supplemental material for Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study

Supplemental material, sj-doc-1-taw-10.1177_20420986251349449 for Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study by Haya M. Almalag, Jawza F. Alsabhan, Abdurhman S. Alarfaj, Eman Alfi, Shorouq Albalawi, Asma A. Al-Shadaawi, Sahar A. Alshehri, Ghadah Asaad Assiri, Ibrahim Almaghlouth and Mohammed A. Omair in Therapeutic Advances in Drug Safety

Supplemental Material

sj-docx-2-taw-10.1177_20420986251349449 – Supplemental material for Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study

Supplemental material, sj-docx-2-taw-10.1177_20420986251349449 for Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study by Haya M. Almalag, Jawza F. Alsabhan, Abdurhman S. Alarfaj, Eman Alfi, Shorouq Albalawi, Asma A. Al-Shadaawi, Sahar A. Alshehri, Ghadah Asaad Assiri, Ibrahim Almaghlouth and Mohammed A. Omair in Therapeutic Advances in Drug Safety

Supplemental Material

sj-docx-3-taw-10.1177_20420986251349449 – Supplemental material for Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study

Supplemental material, sj-docx-3-taw-10.1177_20420986251349449 for Factors related to dosing frequency and route of administration in methotrexate intolerance among patients with rheumatoid arthritis: a cross-sectional study by Haya M. Almalag, Jawza F. Alsabhan, Abdurhman S. Alarfaj, Eman Alfi, Shorouq Albalawi, Asma A. Al-Shadaawi, Sahar A. Alshehri, Ghadah Asaad Assiri, Ibrahim Almaghlouth and Mohammed A. Omair in Therapeutic Advances in Drug Safety

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Haya M. Almalag

Mohammed A. Omair

Supplemental material

Supplemental material for this article is available online.

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