Medication adherence has an impact on disease activity in rheumatoid arthritis: a systematic review and meta-analysis

Figures & data

Figure 1 Flow chart showing selection of studies for inclusion in this meta-analysis.

Abbreviation: IQR, interquartile range.

Table 1 Characteristics of studies included in the meta-analysis

First author, year	Country of study	Number of subjects	Disease duration		Type of study	RA criteria	Proportion adherent	Medication	M-NOS
			Adherent	Nonadherent
Fransen et al, 2004^Citation19	The Netherlands	N=411	NS	NS	RCT	1987 ACR/EULAR	208 (51%)	MTX	3
Contreras-Yanez et al, 2010^Citation16	Mexico	N=93	NS	NS	Cohort study	NS	47 (50.5%)	DMARDs	4
Cannon et al, 2011^Citation17	USA	N=455	9.4±11.7	9.4±10.3	Cohort study	1987 ACR	384 (84.4%)	MTX	4
Richards et al, 2012^Citation3	USA	N=573	17.4±12.0	20.6±13.0	Cohort study	1987 ACR	271 (47.3%)	Bisphosphonate therapy	4
Salaffi et al, 2015^Citation18	Mexico	N=209	5.04±2.60	4.76±2.85	Cohort study	2010 ACR/EULAR	166 (79.4%)	Biologic treatment, (etanercept, adalimumab, golimumab and certolizumab)	4
Arshad et al, 2016^Citation15	Pakistan	N=100	6.10±4.09	6.70±3.55	Cross sectional	1987 ACR	77 (77%)	MTX	1
Xia et al, 2016^Citation20	China	N=122	8.64±9.17	8.84±9.27	Cross sectional	1987/2012 ACR	45 (36.9%)	DMARDs	2

Note: Data presented as mean ± SD unless otherwise indicated.

Abbreviations: ACR, American College of Rheumatology; DMARDS, disease-modifying antirheumatic drugs; MTX, methotrexate; M-NOS, modified version of the Newcastle -Ottawa Scale; NS, not state; RA, rheumatoid arthritis; RCT, randomized controlled trial.

Table 2 Quality assessment of the included studies measured by M-NOS

Study ID	Representativeness	Size	Comparability	Outcome	Statistics	Total
Fransen et al^Citation19	1	1	1	0	0	3
Contreras-Yanez et al^Citation16	1	0	1	1	1	4
Cannon et al^Citation17	1	1	0	1	1	4
Richards et al^Citation3	1	1	0	1	1	4
Salaffi et al^Citation18	0	1	1	1	1	4
Arshad et al^Citation15	0	0	0	0	1	1
Xia et al^Citation20	0	0	0	1	1	2

Notes: Low risk of bias (≥3 points); high risk of bias (<3 points).

Abbreviation: M-NOS, modified Newcastle Ottawa Scale.

Table 3 Meta-analysis of outcome measures

Outcome	Number of studies	Sample size (adherence/nonadherence)	Heterogeneity test		Model selection	MD or SMD	95% CI	P-value
			P-value	I^2 (%)
DAS-28	6	1,033/721	<0.01	87	Random	−0.42	−0.80, −0.03	0.03
ESR	3	476/194	0.27	24	Fix	−7.39	−11.69, −3.08	0.0008
SJC	2	429/148	0.04	76	Random	−0.37	−1.30, 0.56	0.87
TJC	2	429/148	0.25	23	Fix	−1.29	−2.51, −0.06	0.04
VAS	2	429/148	0.70	0	Fix	1.41	−3.68, 6.50	0.59
CRP	4	642/237	<0.01	82	Random	0.35	−0.64, 1.34	0.49

Abbreviations: CRP, C-reactive protein; DAS-28, the 28-joint count disease activity score; ESR, erythrocyte sedimentation rate; MD, mean difference; SJC, 28 swollen joint counts; TJC, 28 tender joint counts; SMD, standard mean difference; VAS, visual analog scale.

Figure 2 Forest plot of disease activity achievement in adherent patients versus nonadherent patients with RA.

Notes: (A) Total score of DAS-28 for RA; (B) ESR for RA; (C) SJC for RA; (D) TJC for RA; (E) VAS for RA; (F) CRP for RA.
Abbreviations: CRP, C-reactive protein; DAS-28, the 28-joint count disease activity score; df, degrees of freedom; ESR, erythrocyte sedimentation rate; IV, independent variable; RA, rheumatoid arthritis; SJC, 28 swollen joint counts; TJC, 28 tender joint counts; VAS, visual analog scale.

Figure S1 Summary of subgroup analysis.

Notes: (A) Subgroup analysis of country. (B) Subgroup analysis of sample size. (C) Subgroup analysis of publication year. (D) Subgroup analysis of study quality. (E) Subgroup analysis of the measurements of medication adherence. ^aNot use scale to measure medication adherence completely, ^bonly use scale to measure medication adherence.

Abbreviations: IV, independent variable; df, degrees of freedom.

Table S1 Summaries of measures for medication adherence and disease activity

First author, year	Adherence methods	Disease activity methods
Fransen et al 2004^Citation2	Adherence was determined from the database, by comparing the prescribed methotrexate (MTX) dose with the dose proposed by the guidelines. If all MTX prescriptions for an individual patient were in congruence with the guidelines, this was determined to be a case of full adherence (FA). A case of non-adherence (NA) was determined if one or more decisions were not in agreement with the guidelines.	The disease activity score (DAS) was calculated using the Ritchie articular index (RAI), a swollen joint count, erythrocyte sedimentation rate (ESR), and general health. The RAI was calculated according to the grading and accumulation described by Ritchie et al,^Citation1 and ranged from 0 to 78.8. The swollen joint count ranged from 0 to 44. General health (GH) and pain were rated on 100 mm visual analog scale (VAS).
Yanez et al 2010^Citation3	The CQ is a 20-items questionnaire (Appendix) that was locally designed. A patient was considered to be CQ-adherent when boxes either 3 (Almost always) or 4 (Always) were filled for items 10 (In the past 2 months, I took my medication exactly at the day/s indicated by my rheumatologist), 11 (In the past 2 months, I took my medication exactly at the day/times indicated by my rheumatologist) and 12 (In the past 2 months, every time I took my medication, I took the precise number of tablets indicated by my rheumatologist). A patient was considered to be CQ-persistent if, in item 8 (In the past 2 months, how often did you completely stop taking your medication?), boxes 0 (Never) or 1 (Almost never) were filled. Patients were defined as adherent/persistent during the study period if scored as adherent/persistent at the three consecutive evaluations. The DRR is a standardized format that records names of actual (taken during the 7 days before the interview) DMARDs and their doses, timing and frequency. A patient was considered as DRR-adherent when the final percentage was 80% and DRR-persistent when taking any dose of the indicated DMARDs for at least 5 consecutive days of the 7 days.	The primary outcome variable was the DAS-28, ESR and C-reactive protein (CRP).
Cannon et al 2011^Citation4	For each patient, the medication possession ratio (MPR) was calculated for the first episode of MTX exposure of a duration of >12 weeks for both new and established MTX users. High MTX adherence was defined as an MPR >0.80 and low MTX adherence was defined as an MPR <0.80.	The primary outcome variable was the DAS-28, Secondary outcome variables evaluated were tender joint count, swollen joint count, patient global disease assessment (100 mm scale), patient pain (10-point scale), physician global disease assessment (100 mm scale), Multidimensional Health Assessment Questionnaire, ESR, and CRP level.
Richards et al 2012^Citation5	Medication adherence was assessed by calculating the medication possession ratio (MPR), defined as the proportion of treatment time that a patient had an available drug. Therefore, for this analysis, subjects were deemed adherent with bisphosphonate therapy if the MPR was ≥0.80 and non-adherent if the MPR was <0.80	Disease activity as measured by the mean Disease Activity Score in 28 joints (DAS-28).
Salaffi et al 2015^Citation6	At baseline, all eligible patients underwent clinical rheumatologic visit in order to acquire data of the disease activity, and determine the biological treatment. After 12 months, we sent the MMAS-4 to the patients to complete, by home address or Internet electronic system (according their comfort). For those with scarce confidence with the Internet, the MMAS-4 was sent by regular mail, whereas for those who chose the Internet system, a telemedical care called “REmote TElemonitoring for MAnaging Rheumatologic Condition and HEalthcare programmes (RETE- MARCHE)” was used. Responses to the MMAS-4 questions are indicated in binary fashion (yes/no). The degree of adherence was determined according to the score resulting from the sum of all the correct answers: high adherence (0 points), average adherence (1–2 points), and poor adherence (3–4 points). Higher scores indicate less adherence.	CDAI, ESR, CRP, SJC, TJC Clinical Disease Activity Index is the only composite index that does not incorporate an acute phase response and can therefore be used to conduct a disease activity evaluation essentially anytime and anywhere. Clinical Disease Activity Index ranges from 0 (totally inactive disease) to 76 (very active disease). Patients can be divided into those at low (CDAI ≤10), moderate (CDAI ≤22), and high disease activity (CDAI >22). Clinical Disease Activity Index of 2.8 or less corresponds to remission.
Arshad et al 2016^Citation7	Adherence was defined as omission of two or less doses of prescribed MTX during the previous 8 weeks. This number was used because two times or less would represent adherence rate of 80% or more which is considered acceptable by most authors. Patients who missed three or more doses were considered nonadherent.	Disease activity on the current visit was calculated by DAS-28 which has four variables; tender joint count, swollen joint count, patient pain VAS and ESR.
Xia et al 2016^Citation8	Adherence was assessed using the CQR. The CQR is a 19-item, self-administered questionnaire, and was developed to correctly identify patients who were classified as “low” adherers (taking, 80% of their medication correctly). The questions were identified through focus groups and clinician’s expert opinion of the likely hindrances to medication taking. The 4-point Likert answering scale ranges from “Definitely don’t agree” (scored 1) to “Definitely agree” (scored 4); items 4, 8, 9, 11, 12, and 19 have to be reversely recoded (4=1, 3=2, etc). Lower scores indicate lower levels of adherence.	Disease activity was estimated with the valid and reliable DAS-28, incorporating 28 swollen and tender joint counts, patient’s assessment of disease activity (0–100 mm VAS, where 0= not active at all and 100= extremely active), erythrocyte sedimentation rate (mm/hour), and CRP (mg/L). The questionnaire was also used to collect concurrent information about disease- related data and general health perception rated on VAS.

Abbreviations: CQ, compliance Questionnaire; DRR, drug record registry; MPR, medication possession ratio; MMAS-4 the original 4-item, Morisky Medication Adherence Scale; CQR, Compliance Questionnaire on Rheumatology; ESR, erythrocyte sedimentation rate; DAS-28, 28-joint count disease activity score; CDAI, Clinical Disease Activity Index; SJC, 28 swollen joint counts; TJC, 28 tender joint counts.

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 Web of Science ®Google Scholar

RichardsJSCannonGWHaydenCLAdherence with bispho-sphonate therapy in US veterans with rheumatoid arthritisArthritis Care Res (Hoboken)201264121864187022740421

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 PubMed Web of Science ®Google Scholar

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 PubMed Web of Science ®Google Scholar

XiaYYinRFuTTreatment adherence to disease-modifying antirheumatic drugs in Chinese patients with rheumatoid arthritisPatient Prefer Adherence20161073574227217726

 PubMed Web of Science ®Google Scholar