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

Abstract

Background: Methotrexate (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. Methods: This 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. Results: Among 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). Conclusions: The 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.

Assessing methotrexate intolerance and its prevalence in rheumatoid arthritis: Development and validation of the MISA questionnaire

“…Similar to other studies, gastrointestinal complaints like nausea were the most common in our study. In our study, MTX intolerance was associated with a younger age which has also been shown by previous studies 9,21,29 . Previously, some studies in juvenile idiopathic arthritis have found parenteral use to be associated with both higher and lower occurrence of intolerance 11,30 .…”

“…In our study, MTX intolerance was associated with a younger age which has also been shown by previous studies. 9,21,29 Previously, some studies in juvenile idiopathic arthritis have found parenteral use to be associated with both higher and lower occurrence of intolerance. 11,30 However, we did not find any such association, perhaps due to a smaller proportion of patients on parenteral MTX in this study.…”

An Overview on Causes of Nonadherence in the Treatment of Rheumatoid Arthritis: Its Effect on Mortality and Ways to Improve Adherence

“…When multiple medications are prescribed, the risk of medication interactions increases along with the risk of AEs [ 28 ]. One study saw that when MTX was combined with frequent corticosteroid use, tolerance to MTX dropped significantly (odds ratio = 2.73; 95% confidence interval, 1.06 to 7.06; p = 0.038) [ 29 ]. When AEs become too severe or frequent, the patient-perceived risk-benefit declines leading to skipped doses or abandonment of the medication altogether [ 5 , 29 ].…”

“…One study saw that when MTX was combined with frequent corticosteroid use, tolerance to MTX dropped significantly (odds ratio = 2.73; 95% confidence interval, 1.06 to 7.06; p = 0.038) [ 29 ]. When AEs become too severe or frequent, the patient-perceived risk-benefit declines leading to skipped doses or abandonment of the medication altogether [ 5 , 29 ]. Even chronic fatigue, a common AE reported from those on multi-pharmacologic treatment regimen, was reported to cause such a detrimental emotional impact that eventually lead to nonadherence [ 5 , 28 ].…”

“…The most commonly reported AEs by physicians were those with respect to laboratory and imaging results, such as cytopenias, interstitial lung diseases, and liver or kidney function impairment [ 26 ]. Additional research showed that when taking MTX, one of the most common medications used in the treatment of RA, nausea was experienced by 92.3% of patients, followed by irritability and restlessness (96.1%), abdominal pain (46.1%), and vomiting (30.7%) [ 27 , 29 ]. However, with these side effects in mind, patients were hesitant to report them for fear of seeming “difficult” or receiving negative feedback from the physician [ 27 ].…”