Methotrexate Intolerance Severity Score Questionnaire Research Articles

Prevalence of methotrexate intolerance among patients with rheumatoid arthritis in Erbil city using methotrexate intolerance severity score

Background and objectives: Rheumatoid arthritis is classified as an autoimmune disease characterized by inflammation of the joints and membranes surrounding the joints. The aim of this study was to find the frequency of methotrexate intolerance among rheumatoid arthritis patients and to detect factors contributing to intolerance. Methods: An observational cross-sectional study was conducted in Rizgary and Hawler Teaching Hospital in Erbil/ Iraq. The study period started from the 1st of July 2021 to the 1st of July 2022. A convenient sample of hundred patients was included in the study. A validated version of the methotrexate intolerance severity score questionnaire was used for data collection. Each element in the methotrexate intolerance severity score questionnaire was given a score ranging from 0-3 depending on the absence of symptoms or the presence of mild, moderate or severe symptoms. The intolerance was diagnosed based on a cut-off score of 6 and more. Results: Females constituted 93% of the sample, 49% were obese, and only 13% were smokers. Among the rheumatoid arthritis patients, 66% tolerated Methotrexate, and only 34% did not tolerate the treatment. The oral dose was tolerated by 71%, and the only significant relation(p=0.050) was reported for the route of Methotrexate administration. The differences were significant for restlessness (p<0.001), crying (p=0.002), irritability(p<0.001), and not taking medication. Conclusions: The study concluded that Methotrexate intolerance is prevalent among Rheumatoid arthritis patients in Erbil city. The prevalence of intolerance was significant among steroid users.

НЕПЕРЕНОСИМОСТЬ МЕТОТРЕКСАТА У ДЕТЕЙ С ЮВЕНИЛЬНЫМ ИДИОПАТИЧЕСКИМ АРТРИТОМ ПО ДАННЫМ ОПРОСНИКА MISS (METHOTREXATE INTOLERANCE SEVERITY SCORE): ОДНОМОМЕНТНОЕ ИССЛЕДОВАНИЕ

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. First-line therapy is the prescription of Methotrexate (MTX) though this drug can cause undesirable effects which in its turn dictates the need for the use of diagnostic techniques that would allow early detection of intolerance to MTX. One of such diagnostic approaches is the Methotrexate Intolerance Severity Score (MISS) questionnaire. The purpose of this research was to evaluate the frequency of MTX intolerance in children with JIA using the Russian-language adaptation of the MISS questionnaire. Materials and methods used: a single-center, single-stage study of children aged 3 to 17 y/o with a non-systemic variant of JIA who were prescribed MTX was conducted using the 2011 MISS questionnaire in Russian. The MTX intolerance was determined if the patient scored 6 points and above. Results: 250 patients (78 boys and 172 girls) were included in the study. MTX intolerance using the MISS questionnaire was identified in 30% of patients; the most common complaint was MTX-associated nausea. The cut-off point for the questionnaire was estimated using the ROC analysis. The area under the ROC curve was 0.945. Patients scoring 6 points with a sensitivity of 94% (95% CI 78-97) and specificity of 100% (95% CI 80-100) were intolerant to MTX. The validity of using the questionnaire to identify individuals with MTX intolerance has been demonstrated therefore the questionnaire can be recommended for wider use. Conclusion: MTX intolerance, which was determined by the total score (6 points and above) was identified in 75 patients on MTX therapy.

Cross-Cultural Adaptation and Validation of the Methotrexate Intolerance Severity Score Questionnaire in Portuguese (Brazil) for Children and Adolescents with Juvenile Idiopathic Arthritis.

The Methotrexate (MTX) Intolerance Severity Score (MISS) questionnaire has been developed to identify MTX adverse events in juvenile idiopathic arthritis (JIA). The objective of this study was to translate and validate MISS into Brazilian Portuguese for children and adolescents. The MISS was translated into Portuguese following the standardized guidelines. We analyzed the following psychometric properties: acceptability, internal consistency, test-retest reproducibility, relative-child reliability, and external criterion and discriminant validity. We included 138 JIA patients (age: 8-18 years) and 108 relatives who took less than 5 min to answer MISS. Reproducibility tested after 15 days was good, with a kappa > 0.76. We observed good internal consistency (Cronbach's coefficient 0.75-0.87 (patients) and 0.75-0.79 (relatives)). Reliability between patients and relatives was good except for stomachache and restlessness. Cut-off points of 5 and 6 had good sensitivity (84 and 71, respectively) and specificity (80 and 87, respectively). Using a cut-off value of 6, we observed 86 (62.3%) MTX-intolerant patients. In conclusion, MISS is a viable and practical tool for routine clinical care to identify MTX intolerance in JIA. Parents do not easily identify stomachache and restlessness as adverse MTX events.

Efficacy of Folinic Acid in Comparison to Folic Acid for Reducing Side Effects of Methotrexate in Children with Juvenile Idiopathic Arthritis

Background: Methotrexate (MTX) is the most effective and commonly used disease-modifying anti-rheumatic drug in the management of juvenile idiopathic arthritis. Several patients develop side effects, which may lead to low quality of life and non-compliance to MTX. To reduce MTX-induced side effects, folic acid supplementation is prescribed by most rheumatologists. Even after that, some patients have symptoms while receiving MTX. Objectives: To assess the efficacy of folinic acid in comparison to folic acid for reducing the side effects of MTX in JIA patients. Material and methods: In this prospective observational study, newly diagnosed cases of JIA who would be getting MTX were included by purposive sampling. Data were collected using a predesigned questionnaire. Among 40 patients, 20 received folinic acid (Group A), and 20 received folic acid (Group B). Disease activity levels were assessed by JADAS-27 (Juvenile Arthritis Disease Activity Score). Contents from the MISS (MTX Intolerance severity score) questionnaire were used to assess the side effects. All patients were evaluated at baseline, 6th, and 12th weeks. Results: There were significant differences in the frequency of MTX-related adverse events between folinic acid (Group A) and folic acid (Group B). Group A patients only had nausea (10% and 15% in the 6th & 12th week respectively) and vomiting (5% at both follow-ups). On the other hand, in addition to nausea (70% and 95% in the 6th & 12th week) and vomiting (20% and 90% in the 6th & 12th week), folic acid group patients had restlessness, crying, and irritability. Self-discontinuation of MTX was present in the folic acid group (5% & 10% in the 6th & 12th week). Improvement of disease activity was more in the folinic acid group. Conclusion: The folinic acid group had significantly fewer side effects. Improvement of disease activity was more and compliance was also better among them. Methotrexate (MTX) is the most effective and commonly used disease-modifying anti-rheumatic drug in the management of juvenile idiopathic arthritis. A number of patients develop side effects, which may lead to low quality of life and non-compliance to MTX. To reduce MTX induced side effects, folic acid supplementation is prescribed by most rheumatologists. Even after that, some patients have symptoms while receiving MTX.

Адаптация и валидация шкалы непереносимости метотрексата MISS у детей с ювенильным идиопатическим артритом: одномоментное поперечное исследование

Background. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. First-line therapy for JIA includes methotrexate (MTX); however, it can cause adverse events, which necessitates early diagnosis of MTX intolerance. The Methotrexate Intolerance Severity Score (MISS) is one of diagnostic instruments that can be used for this purpose. Objective. To validate, customize, and implement the MISS questionnaire into clinical practice. Patients and methods. This cross-sectional study was conducted between January and May 2022 and included 100 JIA patients (32 boys and 68 girls) aged ≤17 years receiving MTX. We validated the MISS questionnaire to evaluate possible adverse events associated with MTX. We performed linguistic and cultural customization of the MISS questionnaire. To assess the reliability of the questionnaire, we calculated the Cronbach's alpha coefficient. Results. Cronbach's alpha coefficient showed that MISS is a reliable tool to detect MTX intolerance. We found that more than a quarter of patients had MTX intolerance with nausea being the most common complaint among the participants. Conclusion. Despite high MTX efficacy in clinical practice, patients often demonstrated poor treatment adherence due to MTXrelated adverse events. It is important to continue the implementation of the Russian version of MISS to ensure early detection of adverse events and timely initiation of adequate treatment. Key words: children, juvenile idiopathic arthritis, methotrexate, Methotrexate Intolerance Severity Score, drug intolerance

Real-world data on MTX tolerance with regimens used in children versus adults.

Methotrexate (MTX) is one of the most commonly used disease-modifying anti-rheumatic drugs which can cause gastrointestinal side effects. MTX intolerance is defined as gastrointestinal and behavioral symptoms occurring before and after MTX administration. This study aims to evaluate and compare the frequency of methotrexate intolerance in adult and pediatric patients. Patients with a rheumatic disease who used oral or parenteral methotrexate for at least 3months were included in the study. Methotrexate intolerance was assessed using the Methotrexate Intolerance Severity Score (MISS) questionnaire and visual analog scale (VAS). In the pediatric patient group, the MISS questionnaire and VAS assessment were applied to both patients and families. A total of 200 patients, 100 of whom were children, were enrolled in the study. The mean age for children and adults were 11.9 (± 3.7) and 52.0 (± 10.9). The prevalence of MTX intolerance was higher in the pediatric group, 64.0 and 10.0% (p < 0.001), respectively. Compared with oral administration, the patients receiving parenteral MTX had a higher proportion of MTX intolerance (p < 0.001). Younger age was the independent risk factor for MTX intolerance. There was a strong correlation between MISS and VAS scores between the evaluations of the patient and the family (p < 0.01, r = 0.95/p < 0.01, r = 0.94). Methotrexate intolerance was higher in childhood. All patients using MTX should be monitored and questioned for signs of intolerance.

High frequency of methotrexate intolerance in longstanding rheumatoid arthritis: using the methotrexate intolerance severity score (MISS)

BackgroundMethotrexate (MTX) intolerance is frequent, and its early identification may impact treatment, leading to timely changes in medication that may promote patient compliance and better control of rheumatoid arthritis (RA). The objective of this study was to identify the frequency of, and risk factors for, MTX intolerance using the Brazilian Portuguese version of the Methotrexate Intolerance Severity Score (MISS) questionnaire in patients with RA.MethodsThis cross-sectional study was performed between April 2018 and April 2019 and enrolled patients with RA in regular use of oral or subcutaneous MTX for at least 3 months. Patients were invited to answer the Brazilian Portuguese version of the MISS questionnaire, and MTX intolerance was defined by a score ≥ 6 points. Age, sex, disease duration, time of MTX use, dose, route of administration, concomitant medications, comorbidities, smoking, and Disease Activity Score for 28joint (DAS28) data were collected from institutional medical records.ResultsAmong 120 patients, 103 (85.8%) were female, the mean age was 61 (±12.5) years, the mean duration of disease was 16 (±10.3) years, and the average duration of MTX use was 7 (±5.5) years. The frequency of MTX intolerance was 21.6%. The most frequent symptoms reported after the use of MTX were nausea (92.3%), abdominal pain (46.1%), and vomiting (30.7%). Behavioral symptoms occurred in 96.1% of patients with MTX intolerance, the most frequent being restlessness and irritability. Patients who used corticosteroids were more likely to develop MTX intolerance than those not using corticosteroids (odds ratio = 2.73; 95% confidence interval, 1.06 to 7.06; p = 0.038). Conversely, increasing age showed marginally significant association with decreased risk of MTX intolerance (p = 0.059).ConclusionsThe use of the MISS questionnaire disclosed high frequencies of anticipatory, associative, and behavioral symptoms in MTX-intolerant patients, and the use of corticosteroid increases the risk of MTX intolerance. We suggest that the MISS questionnaire be used routinely in clinical practice.

Cultural Adaptation and Validation of the Methotrexate Intolerance Severity Score in Brazilian Portuguese for Adults With Rheumatoid Arthritis.

The Methotrexate Intolerance Severity Score (MISS) questionnaire is used to identify intolerance to methotrexate (MTX), but it is not available in the Brazilian Portuguese language. The aim of this study was to adapt and validate the MISS in Brazilian Portuguese. The Brazilian Portuguese version of the MISS was developed following the Guidelines for the Process of Cross-cultural Adaptation of Self-report Measures. The new version was tested in 120 patients with rheumatoid arthritis. For the reliability assessment, the Cronbach α coefficient was used. The receiver operating characteristic curve was constructed with the objective of finding the best cutoff point for MTX intolerance and weighing the sensitivity and specificity. The concordance among the results was analyzed using the κ coefficient and factorial analysis with varimax rotation. This methodological study developed and applied a culturally acceptable Brazilian Portuguese version of the MISS. The MISS questionnaire presented internal consistency classified as "very good" because Cronbach α is equal to 0.83 (95% confidence interval, 0.79-0.87). The suitability of the data for factorial analysis was demonstrated using the Kaiser-Meyer-Olkin sample adequacy test (KMO = 0.723) and Bartlett sphericity test (χ2 = 499.98, p < 0.001). It was observed that a factorial analysis with 3 factors is preferred; the receiver operating characteristic curve of the MISS score was considered the cutoff point at 6 points (sensitivity 100% and specificity 89.4%). The Brazilian Portuguese version of the MISS is valid and reliable for the detection of MTX intolerance in clinical practice.

MISS questionnaire in French version: a good tool for children and parents to assess methotrexate intolerance.

The aim of this study was to assess the relevance for children and parents to use the French-validated version of the methotrexate intolerance severity score (MISS), a measure of methotrexate intolerance for children suffering from juvenile idiopathic arthritis. The French-version MISS was developed following the "Guidelines for the process of cross-cultural adaptation of self-report measures." The new version was tested in families of children with juvenile idiopathic arthritis who completed the questionnaire twice at a 2-week interval. Item correlations, Cronbach's alpha, and kappa coefficients were computed to evaluate acceptability, internal consistency, and reproducibility. A culturally acceptable version to French was obtained. A total of 71 individuals were included from May 2015 to November 2015. The results show very good acceptability: good response rate (80%), few missing data (<1%) and good understanding of parents and children. The inter-item, dimension-item, and inter-dimension correlations were satisfactory (except for "vomiting" items-other items correlation). Cronbach's alpha coefficient was well higher than the usually recommended value of 0.6. The results of validity of internal and external consistencies were satisfactory. We also found good agreement between the test-retest for every family. The empirical discriminative cut-off point of 3 showed a sensitivity of 86% and a specificity of 83%. The MISS questionnaire is quick to complete, easy to use. It can be completed by children or their parents with no significant difference. This validated French-version MISS can help study prevalence and risk factors of methotrexate intolerance, better detect this intolerance, and provide better support for patients on long-term treatment.

Prevalence and Risk Factors for Symptoms of Methotrexate Intolerance in Pediatric Inflammatory Bowel Disease.

Methotrexate (MTX) intolerance is defined as gastrointestinal and behavioral symptoms occurring before or after MTX administration that may lead to treatment discontinuation. The aim of this study was to determine prevalence of MTX intolerance in pediatric inflammatory bowel disease (IBD) using the Methotrexate Intolerance Severity Score developed in rheumatology and to identify risk factors for MTX intolerance. Patients with pediatric IBD followed in the IBD clinic of Sainte Justine Hospital who had received MTX for IBD between 2004 and 2016 and were still actively on MTX were invited to fill out the Methotrexate Intolerance Severity Score questionnaire. A cutoff score of ≥6 points was used to define MTX intolerance, with at least one point for anticipatory, associative or behavioral items. Among 102 pediatric patients with IBD, 32 (31%) patients reported symptoms of MTX intolerance. Using a multivariable logistic regression model, factors that were associated with having symptoms of MTX intolerance were female sex (odds ratio 4.31 [95% confidence interval, 1.37-13.60], P = 0.01), receiving a dose of MTX higher than 20 mg/wk at the time of the questionnaire (odds ratio 4.06 [95% confidence interval, 1.30-12.70], P = 0.02), and having active disease according to Physician's Global Assessment (odds ratio 3.44 [95% confidence interval, 1.15-10.26], P = 0.03). Prophylactic prescription of antiemetics and folic acid did not prevent symptoms of MTX intolerance. Symptoms of MTX intolerance are frequent in pediatric IBD. The Methotrexate Intolerance Severity Score questionnaire could help better recognition of these symptoms. Identification of risk factors could have important implications for the success of treatment.

Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate intolerance severity score (MISS questionnaire).

The objective of the study was to determine the frequency of methotrexate intolerance in rheumatoid arthritis (RA) patients by applying the methotrexate intolerance severity score (MISS) questionnaire and to see the effect of dose and concomitant use of other disease-modifying antirheumatic drugs (DMARDS) on methotrexate (MTX) intolerance. For the descriptive study, non-probability sampling was carried out in the Female Rheumatology Department of Fauji Foundation Hospital (FFH), Rawalpindi, Pakistan. One hundred and fifty diagnosed cases of RA using oral MTX were selected. The MISS questionnaire embodies five elements: abdominal pain, nausea, vomiting, fatigue and behavioural symptoms. The amplitude of each element was ranked from 0 to 3 being no complaint (0 points), mild (1 point), moderate (2 points) and severe (3 points). A cut-off score of 6 and above ascertained intolerance by the physicians. A total of 33.3% of the subjects exhibited MTX intolerance according to the MISS questionnaire. Out of which, the most recurring symptom of all was behavioural with a value of 44% whereas vomiting was least noticeable with a figure of 11%. About 6.6% of the women with intolerance were consuming DMARDs in conjunction with MTX. Those using the highest weekly dose of MTX (20mg) had supreme intolerance with prevalence in 46.2% of the patients. The frequency of intolerance decreased with a decrease in weekly dose to a minimum of 20% with 7.5mg of MTX. MTX intolerance has moderate prevalence in RA patients and if left undetected, the compliance to use of MTX as a first-line therapy will decrease. Methotrexate intolerance is directly proportional to the dose of MTX taken. Also, there is no upstroke seen in intolerance with the use of other disease-modifying agents.

High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: Development and validation of a methotrexate intolerance severity score

To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire. The MTX Intolerance Severity Score (MISS) questionnaire was constructed, consisting of 5 domains: stomach ache, nausea, vomiting, sore mouth, and behavioral symptoms. The domains each consisted of 3 questions pertaining to the presence of a symptom upon, prior to (anticipatory), and when thinking of (associative) MTX intake. The MISS questionnaire was validated in 86 patients by determining its discriminative power between patients with and those without MTX intolerance, identified as such by a gold standard (physician's opinion). Using the MISS questionnaire, the prevalence of MTX intolerance was determined in 297 JIA patients. The MISS questionnaire discriminated well between MTX-intolerant and MTX-tolerant patients. A cutoff score of 6 yielded the best sensitivity (88%) and specificity (80%). MTX intolerance was found in 150 (50.5%) of 297 patients. Of 220 patients receiving oral MTX, 98 (44.5%) experienced MTX intolerance, whereas 67.5% of 77 patients receiving parenteral MTX experienced intolerance to the drug (P = 0.001). Our findings indicate that the MISS questionnaire is a highly sensitive and specific tool for the diagnosis of MTX intolerance, and that there is a high prevalence of MTX intolerance among JIA patients. The prevalence of intolerance in patients receiving parenteral MTX exceeds that in patients receiving oral MTX. The frequent occurrence of anticipatory and associative symptoms suggests that classic conditioning plays an important role in MTX intolerance.