Validation of Methotrexate Intolerance Severity Score (MISS) questionnaire to measure methotrexate intolerance among rheumatoid arthritis Egyptian patients

Background Rheumatoid arthritis (RA) is a systemic autoimmune chronic inflammatory disease, causing progressive disability. Methotrexate (MTX) is the gold standard drug treatment for RA. Long-term use of MTX is associated with intolerance including gastrointestinal effects. In addition, anticipatory, associative, and behavioral symptoms such as anxiety and irritability are also observed which are often inadequately managed, leading to discontinuation of treatment. Methotrexate Intolerance Severity Score (MISS) questionnaire designed to measure MTX intolerance. The work aims to validate the MISS questionnaire Arabic version for the detection of MTX intolerance among Egyptian RA patients to halt the progression of the disease. Results A total of 80 patients were involved in this study. Of those, 67 (83.8%) were females with a mean disease duration of 6.9 ± 6.1 years. Forty-eight patients (60%) were intolerant to MTX and 32 patients (40%) were tolerant. Comparison between the tolerant group ( n = 32) to MTX and the intolerant group ( n = 48) revealed a statistically significant difference between them regarding the DAS28 score and HAQ score. Behavioral intolerance is the predominant factor that directs MTX intolerance. Conclusion The MISS questionnaire has a good predictive ability to detect MTX intolerance among Egyptian RA patients. Due to its good reliability, serves as an invaluable tool as it detects anticipatory and associative symptoms.


Background
Rheumatoid arthritis (RA) is a chronic autoimmune disease with a detrimental effect on quality of life due to irreversible joint damage [1].Methotrexate (MTX) is the gold standard prescribed conventional synthetic (CS) Disease-modifying anti-rheumatic drugs (DMARDs) based on their efficacy, safety, and route of administration.It is endorsed as an initial treatment, as an "anchor drug" in combination with csDMARD, biological DMARD, or targeted synthetic DMARD [2].
MTX inhibits dihydrofolate reductase which is the enzyme required for purine and pyrimidine synthesis [3] causing uncoupling of nitric oxide synthase which increases apoptosis of T cells [4,5].It employs antiinflammatory effects by inhibiting transmethylation reactions required for cellular functions with diminished synovial damage and enhances adenosine release causing inhibition of neutrophil recruitment [6].
The half-life of MTX is short about 6 h [6].Its adverse effects that could limit its use [7] include nausea, vomiting, stomachache, dizziness, and headache termed "MTX intolerance" as occurred in juvenile idiopathic arthritis, psoriatic arthritis, and inflammatory bowel disease [8].Thus, evaluating MTX intolerance to improve patient tolerability is critical [9].
Symptoms may be anticipatory prior to intake, associative when thinking about consuming the drug, or behavioral as anxiety and irritability arising as a conditioned response may develop [10].
MTX Intolerance Severity Score (MISS) questionnaire considers the patient intolerant if the score is ≥ 6 [9].The Arabic version was validated in Saudi Arabian RA patients [11].
Our objective was to validate the MISS questionnaire Arabic version for the detection of MTX intolerance among Egyptian RA patients to halt the progression of the disease.

Material and methods
A cross-sectional study was conducted on 80 adult RA patients who were diagnosed according to the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria (ACR/ EULAR) criteria [12] and were on regular use of MTX therapy for at least 3 months.
The study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki), the study was approved by the Ethics Committee of the hospital and informed written consent was obtained from participants in the study.

Exclusion criteria
Patients suffered from gastrointestinal diseases (such as malignancy or celiac disease), and psychiatric illnesses and were unable to fully understand or unwilling to complete the MISS questionnaire.

Clinical evaluation
Full medical history taking with special concern about MTX dose, duration, route of administration, folic acid dose, other DMARDs, steroids dose, and antiemetic drug.

Health Assessment Questionnaire (HAQ) for daily activities of living
Which comprises 20 questions grouped into 8 subscales and the question's highest score determines the score for the subscale [14].

Methotrexate Intolerance Severity Score (MISS) questionnaire (Arabic version)
It is a 12-item questionnaire constructed to assess MTX intolerance covering 4 aspects of intolerance: stomachache, nausea, vomiting, and behavioral complaints.Its score ranges from 0 to 36 and the patient is considered intolerant if the score is ≥ 6 points with at least 1 point in the anticipatory, associative, and/or behavioral symptoms [11].

Statistical analysis
Data were tabulated and statistically analyzed using SPSS, version 20 (SPSS Inc., Chicago, IL, USA).Quantitative data were described as mean and standard deviation/ median and interquartile range.Independent t test was used to compare quantitative data between independent groups.Qualitative data were expressed as frequencies (n) and percentages (%).Fisher's exact test was used to the relation between qualitative variables.Pearson correlation coefficient (r) was used to correlate between parametric quantitative variables.Logistic regression analysis was done for the detection of variables independently affecting the occurrence of MTX intolerance.Reliability analysis was done by alpha (Cronbach's) coefficient.P value ≤ 0.05 was considered significant.
Forty-eight patients (60%) were intolerant to MTX, and 32 patients (40%) were tolerant.Intolerant patients were 41 (72.9%) female patients and 7 (27.08%)male patients.The most frequently occurring complaint was a refusal to take MTX detected in 56 patients (70%) and 45 patients complained of restlessness (56.3%) followed by nausea after taking MTX occurred in 39 patients (49.5%).Vomiting complaint was the least frequent symptom that occurred in 16 patients (20%) who had vomiting after taking MTX and 7 patients (8.8%) of them had anticipatory symptoms.Distribution of MISS items and scores among the studied RA patients (Table 4).
A statistically significant positive correlation of the MISS questionnaire with the HAQ score was detected (r = 0.298, p value = 0.007), but no correlation was found with the DAS28 score (r = 0.171, p value = 0.130).Comparison between the tolerant group (n = 32) to MTX and the intolerant group (n = 48) detected a statistically significant difference (p < 0.05) between them regarding the DAS28 score and HAQ score.There was no statistical difference between the two groups regarding marital status, menstrual history, education, or job (p > 0.05).Comparison between MTX tolerant and intolerant groups (Table 5).
Logistic regression detected that RF significantly (p < 0.05) increases the risk of MTX intolerance by 0.024 times (Table 6).The reliability of the MISS questionnaire was 0.809 suggesting good internal consistency.

Discussion
Management of RA focuses on improving the quality of life as it is an irreversible disease [2].So, early detection of MTX intolerance is essential and easy as the MISS is a simple and objective questionnaire [15].
If intolerance is due to gastrointestinal symptoms folic acid intake, dose splitting, and shift from oral to parenteral route is considered [16] and if it is due to behavioral symptoms, patient counseling is important [11].
In Egyptian RA patients, 60% of the participants were MTX-intolerant which was higher than the Albaqami et al. [11] study conducted on 185 Saudi Arabian RA and found that 39.5% of them were intolerant.Also, a study on 150 Brazilian RA patients found a prevalence of MTX intolerance of 21.6% [17].
Our findings could be due to a behavioral intolerance, as the MTX is categorized as a chemotherapeutic drug with a negative psychological impression which was supported by the findings in Albaqami et al. [11] as they identified a higher percentage of behavioral intolerance compared to gastrointestinal intolerance.
Also, the higher percentage of intolerance in our study may be due to anticipatory and associative gastrointestinal symptoms which were considered as a conditioned response [18] and could be explained by increased sensitivity of gastrointestinal epithelium due to the buildup of MTX causing nausea and vomiting [10,19] and its stimulation to adenosine receptors in the central nervous system [20,21] and chemoreceptor trigger zone (CTZ) leading to reflex vomiting [22,23].Contrary to Amaral et al. [17], all the patients reported nausea followed by abdominal pain, and then vomiting.Therefore, Cognitive behavioral therapy may benefit in the treatment [8].
Our study included more intolerant female patients than male patients.Similarly, Almalag et al. 2020 assumed that MTX intolerance was linked to the female gender [24] which could be explained by a lower average glomerular filtration rate in females than males.But  as the lower percentage of male gender was included in our study, therefore, results should be interpreted with caution.Also, Bulatović Ćalasan et al. [9] study included 291 RA and psoriatic arthritis (PsA) patients who reported more intolerance in females, but it was statistically insignificant.Regarding caffeine, no association was detected between MTX intolerance and caffeine in our study.While El Nouby et al. [25] and Malaviya [26] reported that caffeine reduced the severe MTX intolerance symptoms which could be explained by that caffeine antagonizes the MTX activation of adenosine receptors in the central nervous system.
We noticed a significant difference in the DAS28 score between the intolerant group and the tolerant group as it was correlated with disease severity.Regarding HAQ, there was a significant positive correlation with MISS score which could be explained by increased level of non-adherence to MTX and missed doses by the patients due to its effect on behavior and gastrointestinal tract.Also, Sherbini et al. [27] noticed an increased risk of MTX cessation after 1-year followup due to adverse effects correlated with a high baseline HAQ [28].
In our study, the most common MTX route was SC followed by IM then oral and we noticed that patients on the SC route were more intolerant.Our findings were similar to Bulatovic et al. [8] and Bulatović Ćalasan et al. [29] who detected that more intolerance on parenteral than on oral MTX which could be due to hatred towards needles causing more behavioral symptoms in the parenteral group [30].Albaqami et al. [11] and Almalag et al. [24] stated that oral intolerance was higher than the SC administration group.
Regarding MTX dose, patients treated with 20 or 25 mg MTX were more intolerant may be due to triggering the CTZ.Similarly, Fatimah et al. [15] noticed that the higher the dose, the more the intolerance.
In our study, there was a higher percentage of MTX intolerance associated with corticosteroid use.Similarly, Amaral et al. [17] stated that corticosteroids may have physiological gastroprotective and pathological proulcerogenic effects.The prolonged action of corticosteroids can be a significant factor in the gastric mucosa [31].Also, Nalwa et al. [18] stated that the use of corticosteroid therapy is a predisposing factor for increased risk of MTX intolerance.
Regarding other drugs combined with MTX doses, there was no significant relation with MTX intolerance which corresponds with Almalag et al. [24] and Fatimah et al. [15].Also, our study was in accordance with Amaral et al. [17] as MTX intolerance was not linked with folic acid deficiency.
Our finding was in accordance with Majorczyk et al. [32] suggested a predictive value of RF for the MTX treatment outcome.In our study, the internal consistency of the MISS questionnaire was similar to Albaqami et al. [11] suggesting its reliability.
Limitations of the study included a small number of patients and most of them were females so other studies are needed with a larger number of male and female patients and explore different parameters such as types of food and different ethnicities.

Conclusion
The MISS questionnaire has a good predictive ability to detect MTX intolerance among Egyptian RA patients.Due to its good reliability, serves as an invaluable tool as it detects anticipatory and associative symptoms.

Table 1
Demographic data of patients

Table 3
Drug history among the studied RA patients MTX methotrexate, SC subcutaneous, IM intramuscular

Table 4
Distribution of MISS items and scores among the studied RA patients

Table 5
Comparison between MTX tolerant and intolerant groups(**) Independent t test, and (!) Fisher exact test was used, P value < 0.05 is considered statistically significant (*).MTX methotrexate, DAS28 disease activity score, HAQ Health assessment questionnaire

Table 6
Logistic regression for detection of independent variables associated with MTX intolerance