The Predictors of and Reasons for Non-Adherence in an Observational Cohort of Patients With Rheumatoid Arthritis Commencing Methotrexate

Holly F. Hope; Kimme L. Hyrich; James Anderson; James Bluett; Jamie C. Sergeant; Anne Barton; Lis Cordingley; Suzanne M. M. Verstappen


Rheumatology. 2020;59(1):213-223. 

In This Article

Abstract and Introduction


Objective: In order to develop interventions to optimize MTX use for the treatment of RA we evaluated the rate of, reasons for and predictors of MTX non-adherence during the first 6 months of therapy.

Methods: The Rheumatoid Arthritis Medication Study (RAMS) is a prospective multicentre cohort study of incident MTX users in the UK. Prior to MTX commencement demographic, clinical and psychological data were collected. A weekly patient-completed diary recorded MTX dose, possible side effects and adherence over 26 weeks. The number of non-adherent weeks was calculated. Potential baseline predictors of ever non-adherence (≥1 week non-adherent) during the first 6 months of MTX therapy were identified using logistic regression analyses.

Results: 606 patients with RA were included; 69% female, mean (S.D.) age 60 (13) years and DAS28 score 4.2 (1.2). Over the first 6 months following MTX initiation, 158 (26%) patients were ever non-adherent (71% intentional, 19% non-intentional, 10% unexplained) and mean (S.D.) number of non-adherent weeks was 2.5 (2.1). Multivariable predictors of ever non-adherence included DAS28 [odds ratios (OR) 1.1, 95% CI 1.0, 1.4], fatigue (OR 1.1, 95% CI 1.0, 1.2 per cm), ≥2 comorbidities vs no comorbidities (OR 1.9, 95% CI 1.1, 3.5) and high medication concerns despite perceived need (OR 1.1, 95% CI 1.0, 1.1 per unit decrease in need/concern differential).

Conclusion: This is the largest study evaluating early intentional and non-intentional non-adherence to MTX, which has identified that patient beliefs and multi-morbidity strongly link with non-adherence. These findings can direct the design of and provide potential targets for interventions to improve patient adherence.


MTX is a recommended first-line conventional synthetic DMARD (csDMARD) for RA.[1–3] Unfortunately, not all patients respond, and this may partially be explained by non-adherence.[4,5] Optimal MTX use involves initiating MTX without delay, adhering to an incremental dose regimen until a treatment response is observed, and then adhering to this maintenance dose with regular blood tests.[1] Optimal MTX use has several benefits including disease control, reducing the need for more expensive biologic treatments and improving overall outcomes for the patient.[6–8] Despite the necessity for quality patient education, current practice is still limited in its effectiveness to improve adherence.[9,10] Tailored adherence interventions to optimize MTX use for patients who may not adhere may therefore improve outcomes.[11]

The first step towards identifying patients who are non-adherent is to accurately measure adherence. In two recent systematic reviews of MTX adherence, rates of adherence to MTX therapy ranged from 59% to 107%, indicating a wide variability in adherence rates and MTX overuse may also be a problem.[12,13] The modal methodology of past studies to measure adherence is pharmacy refill,[14–19] but it is difficult using this method to distinguish between non-adherent patients and those who missed doses in accordance with medical advice, and who should therefore be classified as adherent.[14]

Tailoring interventions involves addressing barriers to adherence. Recent research has identified some of the barriers to MTX initiation,[20] but there is no current research on the reasons for MTX non-adherence. Smaller studies have identified modifiable psychological factors that associate with patient non-adherence after treatment has been initiated and include low perceived need for MTX, maladaptive coping strategies, and low mood.[21–25] In addition, patients' positive expectations of disease outcome prior to commencing csDMARD treatment independently predict adherence.[26] However, there are few large prospective cohort studies with rich data on the clinical and psychological predictors of MTX adherence. Therefore, this analysis, set within a large prospective observational study of patients with RA commencing MTX for the first time, aims to: describe rates of non-adherence to MTX over the first 6 months after therapy commencement; describe the reasons for non-adherence; and identify patient characteristics evident prior to MTX commencement that predict early non-adherence to MTX.