The correlation between 4 adherence measurements methods in patients with rheumatoid arthritis using methotrexate.

AIMS: Methotrexate (MTX) is the cornerstone in the treatment of rheumatoid arthritis (RA) patients. However, adherence to MTX therapy is not optimal, and instruments to assess medication nonadherence are warranted. To date there is no consensus on the best method to determine adherence to MTX. The aim of this study was to assess the correlation between adherence assessed with a Medication Event Monitoring System (MEMS) vs. pill count, MTX-polyglutamate (PG) concentration and Compliance Questionnaire-Rheumatology (CQR) in patients with established RA. Second, the correlations between these methods and the Disease Activity Scores of 28 joints (DAS28) were examined. METHODS: Adult RA patients currently treated with MTX were included. Multivariable linear and logistic regression were used, with adherence assessed with MEMS as dependent variable vs. pill count, MTX-PG concentrations, CQR as independent variables and DAS28 vs. each of the 4 adherence measurements. Covariates were included, such as comedication, age and use of corticosteroids. RESULTS: In total, 190 consecutive RA patients were included. Pill count was correlated with adherence assessed with MEMS (linear regression, ß = 0.588, 95% confidence interval = 0.255-0.921, P < .001), whereas CQR and MTX-PGs were not. Logistic regression confirmed the correlation between dichotomized adherence and pill count only (ß = 4.47, 95% confidence interval = 1.31-7.64, P =  .006). No other correlations were found, either for all adherence outcomes or DAS28. CONCLUSION: Measuring adherence with MEMS is correlated with pill count, whereas other methods were not correlated with MEMS or with DAS28. Pill count can be used to estimate adherence to MTX therapy, in case MEMS is not achievable.

Oral Versus Subcutaneous Methotrexate in Immune-Mediated Inflammatory Disorders: an Update of the Current Literature.

PURPOSE: This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory disorders (IMIDs) through analysis of efficacy, toxicity, pharmacokinetics and pharmacodynamics of both administration routes. RECENT FINDINGS: Recent studies comparing the efficacy of oral versus subcutaneous MTX administration in IMIDs have revealed contradicting results. Some reported higher efficacy with subcutaneous administration, while others found no significant difference. Regarding toxicity, some studies have challenged the notion that subcutaneous administration is better tolerated than oral administration, while others have supported this. Pharmacokinetic studies suggest higher plasma bioavailability and increased accumulation of MTX-polyglutamates (MTX-PGs) in red blood cells (RBCs) with subcutaneous administration during the initial treatment phase. However, after several months, similar intracellular drug levels are observed with both administration routes. There is no conclusive evidence supporting the superiority of either oral or subcutaneous MTX administration in terms of efficacy and adverse events in IMIDs. Subcutaneous administration leads to higher plasma bioavailability and initial accumulation of MTX-PGs in RBCs, but the difference seems to disappear over time. Given the variable findings, the choice of administration route may be based on shared decision-making, offering patients the option of either oral or subcutaneous administration of MTX based on individual preferences and tolerability. Further research is needed to better understand the impact of MTX-PGs in various blood cells and TDM on treatment response and adherence to MTX therapy.

Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate.

Methotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low-dose MTX therapy. We investigated the association and interpatient variability between RBC-MTX-PG3-5 -exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic-pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX-PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX-PG3-5 and DAS28. The median MTX-PG3-5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6-43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9-41.2; n = 351). Clearance of MTX-PG3-5 from RBCs was 28% lower (95% confidence interval (CI): 23.6-32.8%) in a woman and 10% lower (95% CI: 7.7-12.4%) in a 65-year-old compared with a 35-year-old patient. MTX-PG3-5 concentrations associated with DAS28: half-maximal effective concentration (EC50 ) was 9.14 nmol/L (95% CI: 4.2 nmol/L-14.1 nmol/L). EF at 80% (EC80 ) above 47 nmol/L was regarded as the optimal response. Independent of the MTX-PG 3-5 - response association, co-administration of disease-modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax )), whereas smoking, high body mass index and low albumin decreased Emax . In patients with RA starting MTX, RBC-MTX-PG3-5 was associated with clinical response. A dose increase is suggested when MTX-PG3-5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3 months onwards.

A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis.

AIMS: In immune-mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first-line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta-analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX-PG) in erythrocytes and efficacy as well as toxicity across IMIDs. METHODS: Studies analysing MTX-PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta-analyses were performed resulting in several summary effect measures: regression coefficient (ß), correlation coefficient and mean difference (of MTX-PG in responders vs. nonresponders) for IMIDs separately and collectively. RESULTS: Twenty-five studies were included. In RA and JIA, higher MTX-PG was significantly associated with lower disease activity at 3 months (ß: -0.002; 95% confidence interval [CI]: -0.004 to -0.001) and after 4 months of MTX use (ß: -0.003; 95% CI: -0.005 to -0.002). Similarly, higher MTX-PG correlated with lower disease activity in psoriasis (R: -0.82; 95% CI: -0.976 to -0.102). Higher MTX-PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2 nmol/L MTX-PGtotal ; P < .01). CONCLUSION: We showed that higher concentrations of erythrocyte MTX-PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs.

Are Health Care Professionals' Implicit and Explicit Attitudes Toward Conventional Disease-Modifying Antirheumatic Drugs Associated With Those of Their Patients?

OBJECTIVE: It is generally unknown how the attitudes and beliefs of health care professionals (HCPs) might affect the attitudes, beliefs, and medication-taking behavior of patients with rheumatoid arthritis (RA). This study aims 1) to examine the attitudes, health-related associations (both implicit and explicit), and beliefs of HCPs about conventional disease-modifying antirheumatic drugs, and 2) to assess whether these attitudes, health-related associations, and beliefs of HCPs are associated with those of their patients, with their patients' medication-taking behavior, and disease activity. METHODS: HCPs were recruited from 2 centers that specialized in rheumatology across The Netherlands, and patient recruitment followed. In this observational study, implicit outcomes were measured with single-category implicit association tests, whereas explicit outcomes were measured with a bipolar evaluative adjective scale and the Beliefs About Medicines Questionnaire-Specific. Spearman's rank correlations were used to describe correlations between implicit and explicit measures of the attitudes of HCPs. Multilevel, mixed-effects linear models were used to examine the association of HCP-related characteristics, including the implicit and explicit outcomes of HCPs, with those of their patients, their medication-taking behaviors, and disease activity. RESULTS: Of the 1,659 initially invited patients, 254 patients with RA (mean age 62.8 years, mean disease duration 11.8 years, and 68.1% of the patients were female) who were treated by 26 different HCPs agreed to participate in this study. The characteristics, attitudes, health-related associations, and beliefs about medicines of HCPs were not significantly associated with those of their patients, nor with their medication-taking behaviors or disease activity scores. CONCLUSION: This study demonstrated that the attitudes, health-related associations (as measured both implicitly and explicitly), and beliefs of HCPs were not significantly associated with the attitudes, beliefs, medication-taking behavior, and disease activity of patients with RA.

Patient-Reported Burden of Adverse Drug Reactions Attributed to Biologics Used for Immune-Mediated Inflammatory Diseases.

INTRODUCTION: Although the burden of adverse drug reactions (ADRs) has a significant impact on patients' quality of life, thorough knowledge about patients' perspectives on the burden of ADRs attributed to biologics is lacking. OBJECTIVES: This study was conducted to gain insight into the patient burden of ADRs experienced with biologic use. METHODS: The Dutch Biologic Monitor is a prospective, multicentre, event monitoring cohort system including information collected by web-based questionnaires from patients using biologics, mainly for immune-mediated inflammatory diseases (IMIDs). Patients were asked to complete bimonthly questionnaires on biologics used, indication for the biologic, experienced ADRs, consequences of ADRs and burden on a five-point Likert-type scale, ranging from 1 (no burden) to 5 (very high burden). We assessed potential factors associated with patient-reported burden of ADRs. RESULTS: A total of 1355 patients completed 6293 questionnaires between 1 January 2017 and 1 May 2019. Almost half of the patients (665 patients, 49%), 69% with rheumatic diseases and 31% with other diseases, collectively reported 1720 unique ADRs. Infections and musculoskeletal complaints were the most burdensome ADRs and injection-site reactions were the least burdensome. ADRs leading to healthcare professional contact were more burdensome than ADRs without healthcare professional contact. Smoking, respiratory and psychiatric comorbidities were associated with higher burden of ADRs. Crohn's disease, use of adalimumab and use of sulfasalazine as combination therapy were associated with lower burden of ADRs. CONCLUSIONS: The patient perspective gives important insights into the burden of ADRs experienced with biologics. This information could be used by healthcare professionals to optimise treatment with biologics.

Patients with inflammatory rheumatic diseases: quality of self-reported medical information in a prospective cohort event monitoring system.

OBJECTIVES: Assessment of the quality of patient-reported medical information in the Dutch Biologic Monitor and evaluation of the representativeness of the sampled participants. METHODS: Consecutive adult patients using a biologic DMARD (bDMARD) for an immune-mediated inflammatory disease were included in eight Dutch centres. For this substudy, data of 550 patients with inflammatory rheumatic diseases were used. Patient-reported bDMARD prescription, indication and combination therapy were verified for patients that permitted access to their electronic health record using percentage agreement and/or Cohen's kappa (n = 483). Conservative post hoc sensitivity analysis was performed to account for missing data. Population representativeness was tested for the entire substudy population by comparing age, gender and prescribed bDMARD to the centres' reference populations using Mann-Whitney U-test, χ2 goodness-of-fit or Fisher's exact test with Monte Carlo simulation (n = 550). RESULTS: The correct bDMARD was reported by 95.8% of the participants. Agreement between patients and electronic health record was almost perfect for indications (κ = 0.832) and substantial for combination therapies (κ = 0.725). Agreement on combination therapies remained substantial after post hoc sensitivity analysis (κ = 0.640). Gender distribution (P > 0.05) and bDMARD use (P > 0.05) were similar to the reference populations. Median age was different (58.0 vs 56.0 years, P = 0.04), but considered clinically irrelevant. CONCLUSION: The Dutch Biologic Monitor seems to be a valid tool to obtain patient-reported medical information. Reported medical information generally corresponded to the electronic health records and the participants represented their reference populations regarding age, gender and prescribed bDMARD.

Development and Validation of a Sensitive UHPLC-MS/MS-Based Method for the Analysis of Folylpolyglutamate Synthetase Enzymatic Activity in Peripheral Blood Mononuclear Cells: Application in Rheumatoid Arthritis and Leukemia Patients.

BACKGROUND: Folylpolyglutamate synthetase (FPGS) is a crucial enzyme in both cellular folate homeostasis and the intracellular retention of folate analogue drugs such as methotrexate (MTX), which is commonly used for the treatment of (pediatric) leukemia and the anchor drug in rheumatoid arthritis (RA) treatment. To date, assessment of FPGS catalytic activity relies on assays using radioactive substrates that are labor-intensive and require relatively large numbers of cells. Here, we describe a nonradioactive, ultra-high-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS)-based method allowing for sensitive and accurate measurements of FPGS activity in low cell numbers (ie, 1-2 × 10) of biological specimens, including leukemic blast cells of acute lymphoblastic leukemia patients and peripheral blood mononuclear cells of patients with RA. METHODS: The UHPLC-MS/MS assay was validated with 2 CCRF-CEM human leukemia cells, one proficient and one deficient in FPGS activity. Linearity of time and protein input were tested by measuring FPGS activity at 30-180 minutes of incubation time and 10-300 mcg protein extract. In addition, FPGS enzyme kinetic parameters were assessed. RESULTS: The FPGS enzymatic assay showed a linear relation between FPGS activity and protein input (R ≥ 0.989) as well as incubation time (R ≥ 0.996). Moreover, the UHPLC-MS/MS method also allowed for evaluation of FPGS enzyme kinetic parameters revealing Km values for the substrates MTX and L-glutamic acid of 64 µmol/L and 2.2 mmol/L, respectively. The mean FPGS activity of acute lymphoblastic leukemia blast cells (n = 4) was 3-fold higher than that of CCRF-CEM cells and 44-fold and 88-fold higher than that of peripheral blood mononuclear cells from MTX-naive (n = 9) and MTX-treated RA patients (n = 6), respectively. CONCLUSIONS: Collectively, given its sensitivity with low cell numbers and avoidance of radioactive substrates, UHPLC-MS/MS-based analysis of FPGS activity may be eligible for routine therapeutic drug monitoring of MTX in RA and leukemia for therapy (non)response evaluations.

Efficacious transition from reference infliximab to biosimilar infliximab in clinical practice.

OBJECTIVES: To evaluate the transition from reference infliximab Remicade to biosimilar Remsima in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA). METHODS: Patients were informed through a letter about the transition to a biosimilar and were subsequently contacted for possible additional questions and whether they agreed upon the transition. Once agreed, Remsima was administered at the same dosage and interval as previous treatment with Remicade. Data on the transition were analyzed in January 2018. The primary outcome was the percentage of patients continuing treatment with Remsima and secondary outcome was the change in disease activity measured with the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). In addition, the reasons for discontinuation with infliximab or restarting Remicade were recorded. RESULTS: In total 47 patients were approached, 45 patients switched from Remicade to Remsima, two patients disagreed upon transition and continued Remicade. At the end of the follow-up period of 2 years, 39 patients (87%) continued with Remsima, three patients (7%) restarted Remicade due to inefficacy according to the patient (this was not objectified by the rheumatologist) 2 (4%) patients switched to another biological due to lack of effect and in one patient (2%) infliximab was stopped because of lung malignancy. Furthermore, the DAS28-ESR remained comparable before and after the switch, with a mean (SD) of 2.34 (±1.02) and 2.31 (±1.11) respectively. CONCLUSION: In our population, 87% of patients continued Remsima during the follow-up period of approximately 2 years. Three patients restarted Remicade, while retaining stable DAS28-ESR.