Study design
This cross-sectional study was conducted in four hospitals: Showa University Hospital, Showa University Northern Yokohama Hospital, Showa University Fujigaoka Hospital, and Kanto Rosai Hospital. Data collection was conducted only once during the survey.
Patient population
Participants were outpatients who met the 2010 ACR criteria for RA [20]. The inclusion criteria were age ≥ 20 years and consumption of oral MTX for ≥ 3 months. The exclusion criteria were patients with dementia, restlessness, and severe psychiatric disorders. Consecutive sampling was employed. Patients were recruited between August 2013 and October 2014.
Outcome
The primary outcome was the distribution of MTX adherence according to MMAS-8 at the time of the survey based on the patient’s description. MMAS-8 consists of an eight-item questionnaire [21,22,23]. MMAS-8 scores range from 0 to 8 and are classified as follows: low, < 6; medium, > 6 and < 8; and high, 8. Originally, MMAS-8 was developed for daily administration of oral medicine. MTX was administered once a week; thus, we developed the Japanese questionnaire for MTX accordingly after obtaining the original developer’s permission. First, a physician (N.Y.), a pharmacist (T.K.) with experience in scale development translated the scale into Japanese. Second, it was back-translated into English by two professional translators. N.Y., T.K. and two professional translators compared the items with the original items, and discussed the questionnaire and achieved a consensus, and revised the translated and back-translated versions. Finally, we were sent to the original author to confirm the semantic content, and some minor improvements were made. The final version was approved by the original author. Then, five Japanese RA participants took part in a pilot test to see if they could understand the questions and respond to them clearly, if the language was clear, if there were any technical or strange words that the subjects couldn't understand, and if the questions were appropriate for Japanese culture.
Data collection
Social desirability is typically assessed using the Social Desirability Scale (SDS) developed by Crowne and Marlowe in 1960, with 33 items [24]. By "the urge to seek acceptance by acting in a culturally relevant and acceptable way," this scale defines social desirability. Furthermore, a 13-item SDS was developed with confirmed validity and reliability [25,26,27]. In this study, we used the 13-item SDS. The responses are recorded on “True” or “False. Add 1 point to the score for each “True” response to statements 5, 7, 9, 10, and 13. Add 0 points to the score for each “False” response to these statements. Add 1 point to the score for each “False” response to statements 1, 2, 3, 4, 6, 8, 11, and 12. Add 0 points to the score for each “True” response to these statements. The score by domains ranges from 0 to 13. Higher scores indicated higher social desirability.
MTX dose, MTX dosing frequency, duration of MTX treatment were collected. RA disease activity was assessed using the Disease Activity Score in 28 joints (DAS28-ESR). [28]. Activities of daily living (ADL) was assessed using the modified Health Assessment Questionnaire (mHAQ), which is a self-reported questionnaire that measures function, including ADL performance. Depression state was defined using the Centre for Epidemiological Studies-Depression (CES-D) scale[29]. The patient’s perceptions towards medications were assessed using the Belief about Medicines Questionnaire-Specific (BMQ-specific), which includes two domains, BMQ-Specific necessity (5 items) and BMQ-Specific concern (5 items). We used the BMQ necessity-concern differential (“BMQ-Specific necessity” minus “BMQ-Specific concern”) predicted adherence most strongly in studies affecting adherence [30]. Pain severity was assessed using the Brief Pain Inventory (BPI).We used the average numerical rating scale (NRS) pain score other clinical studies have applied in the multivariable analysis. Short Form-8 (SF-8) is a health-related quality of life (QoL) questionnaire [31, 32] We used two summary scores: mental component summary (MCS; showing mental status) and physical component summary (PCS; showing physical status). The Japanese versions of mHAQ, CES-D, BMQ, BPI, SDS, and SF-8 were validated [33, 34].
Additionally, we obtained data on SES, including marital status, educational level, employment status, and living status. Data on patient characteristics, medication, and SES were further collected using questionnaires. Other data were obtained from medical chart records. After consulting the doctor, the participants answered the Morisky Medication Adherence Scale (MMAS-8), mHAQ, CES-D, BMQ, BPI, SDS, SF-8, and SES questionnaires; they returned the completed questionnaires to the data center by mail.
Statistical analyses
MMAS-8, sex, CES-D, and SES were used as categorical variables, whereas age, MTX dose, MTX dosing frequency, duration of MTX treatment, disease duration, DAS28-ESR, mHAQ, BMQ, BPI, SDS, and SF-8 were used as continuous variables. Summary statistics were presented as median with interquartile range (IQR) and numbers with proportion (%). First, we evaluated the distribution of MTX adherence according to MMAS-8. Subsequently, we compared MMAS-8 and pre-described factors using one-way analysis of variance (ANOVA), Kruskal–Wallis test, and chi-squared test. For significant factors, we conducted a trend analysis. Finally, multiple linear regression analysis was performed to exploratively assess factors associated with MTX adherence The co-variables selected were as follows: age, sex, disease duration, RA disease activity (DAS28-ESR), depression state (CES-D), reliability of the medication (BMQ necessity-concern differential), social desirability (SDS), educational level (more than, equal to college-level, or not), and employment status (full-time work or not). These factors were further selected based on previous studies and clinical importance [4, 7,8,9,10,11, 35,36,37]. To compare the mean DAS-28 scores among the three groups using ANOVA, the effect size (small, 0.1; medium, 0.25; and large: 0.4) customarily proposed by Cohen [38] was set at medium (0.25), the significance level was set at 5% on both sides, and the power was set at 80%. The total number of cases was calculated to be 159. The target number of cases was 176, assuming a dropout rate of 10%.
To deal with missing values, we used multivariable multiple imputations with chained equations methods to increase power and minimize selection bias since we considered missing data to be an assumption of missing at random. We included age, sex, disease duration, RA disease activity, depression state, reliability of the medication, social desirability, educational level, and employment status for each imputation model. We generated 10 imputed datasets and combined coefficient estimates using Rubin’s rules for each imputation.
A two-sided p-value < 0.05 was considered statistically significant. All statistical analyses were conducted using STATA 14.2 (StataCorp LP, College Station, TX) software.
Ethical considerations
The ethics committee of Showa University Hospital (approval number 1446) and Showa University Toyosu Hospital, Showa University Northern Yokohama Hospital, Kanto Rosai Hospital approved this study, and informed consent was obtained from all participants before study enrolment. All study procedures were performed in accordance with the Declaration of Helsinki. Patient information was anonymized and de-identified before analysis.