Abstract
Objectives: To assess real-world infusion times for golimumab (GLM-IV) and infliximab (IFX) for rheumatoid arthritis (RA) patients and factors associated with treatment satisfaction.
Methods: An observational study assessed infusion time including: clinic visit duration, RA medication preparation and infusion time, and infusion process time. Satisfaction was assessed by a modified Treatment Satisfaction Questionnaire for Medication (patient) and study-specific questionnaires (patient and clinic personnel). Comparative statistical testing for patient data utilized analysis of variance for continuous measures, and Fisher’s exact or Chi-square test for categorical measures. Multivariate analysis was performed for the primary time endpoints and patient satisfaction.
Results: One hundred and fifty patients were enrolled from six US sites (72 GLM-IV, 78 IFX). The majority of patients were female (80.0%) and Caucasian (88.7%). GLM-IV required fewer vials per infusion (3.7) compared to IFX (4.9; p = .0001). Clinic visit duration (minutes) was shorter for GLM-IV (65.1) compared to IFX (153.1; p < .0001), as was total infusion time for RA medication (32.8 GLM-IV, 119.5 IFX; p < .0001) and infusion process times (45.8 GLM-IV, 134.1 IFX; p < .0001). Patients treated with GLM-IV reported higher satisfaction ratings with infusion time (p < .0001) and total visit time (p = .0003). Clinic personnel reported higher satisfaction with GLM-IV than IFX specific to medication preparation time, ease of mixing RA medication, frequency of patients requiring pre-medication, and infusion time.
Limitations: Findings may not be representative of care delivery for all RA infusion practices or RA patients.
Conclusions: Shorter overall clinic visit duration, infusion process, and RA medication infusion times were observed for GLM-IV compared to IFX. A shorter duration in infusion time was associated with higher patient and clinic personnel satisfaction ratings.
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory condition affecting ∼1% of the world’s populationCitation1. In the US, estimates suggest 1.3–1.5 million individuals have RACitation2,Citation3, and its prevalence is reported to exceed that of other autoimmune diseases including Crohn’s disease, Type I (insulin-dependent) diabetes, lupus, or multiple sclerosisCitation4. Rheumatoid arthritis is characterized by persistent synovitis, systemic inflammation, and development of autoantibodies in some patientsCitation5,Citation6.
Due to the debilitating nature of the disease, individuals with RA report high rates of reduced work productivity, presenteeism, and absenteeism—as many as 30 days per yearCitation7–9. The goal of RA therapy is to achieve relief from the pain, stiffness, and swelling caused by the condition. The biologics golimumab (intravenous; GLM-IV) and infliximab (IFX) are the only intravenously infused anti-tumor necrosis factor (anti-TNF) alpha inhibitors indicated for the treatment of moderate-to-severe RA in combination with methotrexate. However, differences in GLM-IV and IFX preparation, dosing, and administration to RA patients, as outlined in the package inserts, as well as protocols, procedures, and practices of facilities that administer these medications, may lead to differences in efficiency of the infusion session, and may impact patient and provider satisfaction. There are several notable differences between GLM-IV and IFX. First, GLM-IV provides a weight-based dose that is fixed at 2 mg/kg, while IFX allows a weight-based dose varying from 3–10 mg/kg for RA patients. Second, the GLM-IV vial is supplied as a 50 mg dose as a liquid and does not require reconstitution, while the IFX vial is supplied as a 100 mg dose of lyophilized powder which requires reconstitution. Third, GLM-IV is recommended to be infused over 30 minutes, while the recommended infusion duration for IFX is over a period of at least 2 hours.
Efficiency and satisfaction are two of six key areas essential for delivering quality-based healthcare cited by The Institute of MedicineCitation10. Globally, there is little published evidence of studies that evaluate efficiency for RA biological therapies and no direct comparisons conducted in the USCitation11,Citation12. Therefore, we conducted an observational study to determine the time components required to administer GLM-IV and IFX in US patients with a diagnosis of RA, and to assess patient and clinic personnel satisfaction with the time and process of administration of the products.
Methods
Study design
The study was a non-randomized, cross-sectional, observational study of a single GLM-IV or IFX infusion visit in adult patients with RA. The study was conducted at six US sites from August 15, 2016 through November 21, 2016 at four rheumatology physician offices and two free-standing infusion centers. The study observed infusions based on the rheumatologist’s treatment decision prior to patient enrollment. The study did not require changes to the patient’s current medication care plan.
Site recruitment
Before site activation, each principal investigator or applicable clinic personnel completed a feasibility questionnaire addressing the following topics: patient scheduling, medication preparation procedures, and staff research capabilities. Geographic variability was also considered during site recruitment of the study.
Each site consented to allow the research partner staff (Covance Market Access) to observe a single infusion process per enrolled patient. The sponsor was blinded to the identity of sites included in the study, and the sites were blinded to the identity of the sponsor. Research staff noted and reported adverse events in patients consistent with general training and the protocols of the sponsor.
Patient recruitment
Patients who had a prescription for GLM-IV or IFX were pre-identified by designated sites for inclusion and willingness to participate in the study as part of the pre-scheduling process. On the day of their routine visit, patients provided written informed consent, were screened against inclusion and exclusion criteria as well as additional screener questions given by clinic personnel, and, if eligible, were enrolled into the study. Patients received up to $40, in the form of a gift card, for participation in both the infusion observation and post-observation survey.
Individuals eligible for inclusion were men and women, ≥18 years of age, receiving GLM-IV or IFX as prescribed by a rheumatologist for treatment of RA. Patients were excluded from the study if they were pregnant or nursing; were unsuited for infusion of anti-TNF medication on the date of the observation, in the opinion of his/her physician; had a diagnosis of Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, or psoriasis; or were a participant in another experimental, interventional, or non-observational study in the 6 months prior to this study.
Assessment of time-related study variables
Time-related study variables and definitions are summarized in including: clinic visit duration, medication preparation time, patient preparation time, RA medication infusion time, and infusion process time. RA medication time and infusion process time were the primary end-points for the study. Accurate recording of time variables was documented in a case report form (CRF) by a research observer using a synchronized smartphone stop watch. The CRF content was later recorded in an online data collection system.
Table 1. Time-related study variable definitions.
Assessment of satisfaction
Satisfaction was assessed at the patient and clinic personnel level. After infusion was complete, patients were given the opportunity to participate in a computer-based patient questionnaire at the rheumatology office/infusion facility or soon after their study visit. For patients who elected to complete the questionnaire at a more convenient time, an email with a secure access link was provided. The questionnaire included the Treatment Satisfaction Questionnaire for Medication-Intravenous RA, version 1 (TSQM-IV RA, given as a Likert scale, 1–7)Citation13, as well as questions related to treatment and infusion process satisfaction (given as a Likert scale, 0–10). Patients were also queried regarding factors positively and negatively affecting the level of satisfaction with their study infusion visit including: frequency of infusions, length of infusion process, cost of infusion, interactions with clinic personnel during the infusion process, interactions with other patients during the infusion process, convenience of scheduling appointment, location of infusion center, and clinic personnel. Clinic personnel involved in the infusion process were asked to complete a one-time questionnaire during the patient enrollment period about aspects of the infusion process and medications (Likert scale, 0–10), as well as additional questions regarding treatment preference.
Ethics
The study was approved by a central independent review board (IRB), The Copernicus Group (Durham, NC). Each IRB-approved site received the protocol; informed consent form; and patient, clinic personnel, and site questionnaires. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and applicable regulatory requirements.
Statistical methods
As the study was observational, no formal sample size calculations were conducted. The study aimed to enroll a convenience sample of ∼75 patients each for the GLM-IV and IFX groups (total, n = 150). All statistical procedures were conducted in SAS (SAS Institute, Cary, NC). No imputation of missing data was undertaken. The analyses were largely descriptive in nature and included the mean, standard deviation (SD), median, and range, for continuous variables and percentages for categorical variables. Comparative statistical testing for patient data utilized analysis of variance for continuous measures and Fisher’s exact or Chi-square test for categorical measures. As the analyses were considered exploratory, no adjustments for multiplicity were undertaken. Due to the small sample size for the clinic personnel data, no formal statistical comparisons were performed.
Stratified analyses by treatment group were used to minimize confounding. Although the results were generally descriptive, adjustments were undertaken to ensure (as much as possible) that differences in the primary time end-points and patient satisfaction were not confounded by patient or site characteristics. RA medication preparation and infusion time, infusion process time, and patient satisfaction were compared across treatments using a mixed model adjusting for site as a random effect and the following fixed effects for (1) time end-points: age, time since RA diagnosis, number of vials per infusion, prescribed dose (mg/kg), pre-medication (yes/no), patient type (induction vs maintenance on current biologic), and amount of wait time (time arrived in clinic until patient entered the infusion area, minutes) and (2) patient satisfaction: age, number of vials per infusion, number of prior infusions (0, 1, 2, 3–10, more than 10), distance traveled to the site, pre-medication (yes/no), patient type (induction vs maintenance on current biologic), amount of wait time (time arrived in clinic until patient entered the infusion area, minutes), total infusion time, medication stopped (yes/no), satisfaction with cost of medication, infusion experience typical of prior experiences, or previous medication experience (subcutaneous, IV, oral). The least squares means of the treatment difference were evaluated from this model.
Results
A total of 151 patients were screened and 150 patients were enrolled from six sites; of these, 72 received GLM-IV and 78 received IFX. The distribution of patients by treatment group was nearly balanced at each site, with the exception of Site 6 (Supplementary Table).
Demographic characteristics by treatment group and for the overall study cohort are summarized in . Briefly, the majority of patients were female (80.0%) and Caucasian (88.7%), and the mean weight was similar between the treatment groups. Notable differences in baseline characteristics were observed between the GLM-IV and IFX cohorts: on average, patients receiving GLM-IV were younger compared to patients receiving IFX (p = .0105) and there was a lower proportion of retirees in the GLM-IV treatment group compared to the IFX treatment group, with a significant difference observed in employment status between GLM-IV and IFX (p = .0033).
Table 2. Patient demographics by treatment group.
Patient medical and treatment history
A summary of relevant patient medical history and experience is given in . Overall, the mean time since diagnosis of RA was ∼126 months, and more than half of patients reported current methotrexate use (55.3%). Of note, the mean time since first use of the study infusion medication to current infusion treatment was significantly lower for GLM-IV (11.2 months) compared to IFX (49.2 months; p < .0001). Additionally, the majority of patients reported use of at least three previous RA biologics (80.0%); however, the distribution of previous RA biologic use significantly differed between the GLM-IV and IFX cohorts, with IFX having a history of using more prior biologics compared to GLM-IV (p < .0001). Mean RA medication dose per patient was consistent with the prescribing information in the product package insert (2.0 mg/kg for the GLM-IV cohort and 5.5 mg/kg for the IFX cohort).
Table 3. Patient medical and treatment history.
Clinic visit duration
Overall, mean clinic visit duration was significantly reduced for GLM-IV (65.1 min) compared to IFX (153.1 min; p < .0001). Individual components of infusion visit timing (medication preparation, patient preparation, RA medication infusion, and infusion process) are summarized below.
Medication preparation time
Total medication preparation time was significantly lower for GLM-IV (4.2 min) compared to IFX (5.9 min; p = .0059). GLM-IV patients required fewer vials per infusion (mean of 3.7 vials) compared to IFX (mean of 4.9 vials; p = .0001); notably, per the product package insert, GLM-IV is liquid and requires no reconsitiution, while IFX is powder requiring reconstitution.
Patient preparation time
Overall, total patient preparation time was similar for GLM-IV (8.7 min) and IFX (9.1 min). A summary of pre-medication use is included in . Briefly, oral pre-medication administration was provided to fewer GLM-IV patients (20.8%) than IFX patients (44.9%; p = .0019). Likewise, intravenous pre-medication was provided to fewer GLM-IV patients (1.4%) than IFX patients (34.6%; p < .0001). Additionally, a lower proportion of GLM-IV patients (5.6%) reported pre-medication was taken prior to arriving at the infusion clinic as compared to IFX patients (33.3%; p < .0001). Differences in time spent administering oral pre-medications by clinic personnel were significant between GLM-IV (0.3 min) and IFX (0.5 min; p = .0106), although the difference may not be clinically meaningful.
RA medication infusion time
Total infusion time for RA medication, excluding medication stop time, significantly differed between GLM-IV (32.8 min) and IFX (119.1 min; p < .0001, ). Significantly fewer patients receiving GLM-IV (0%) experienced a RA medication stop than patients receiving IFX (10.3%; p = .0067). Inclusion of RA medication stop time did not significantly impact total infusion time. Total infusion time for RA medication, including medication stop time, was 32.8 min for GLM-IV and 119.5 min for IFX (p < .0001). After adjusting for confounders, the least squares mean (standard error [SE]) for RA medication infusion time remained significantly different (p < .0001) between GLM-IV (35.2 [3.4] min) and IFX (120.3 [2.9] min).
Figure 1. (a) RA medication infusion by time. RA medication infusion time was calculated as the time the nurse confirms initiation of the RA medication drip to when the nurse verifies conclusion of the medication drip. Infusion process time was calculated as the sum of the total time for RA infusion medication preparation, time for patient preparation and time required for RA medication infusion. (b) Changes to RA infusion during routine monitoring.
Abbreviations: GLM, golimumab; IFX, infliximab; IV, intravenous; RA, rheumatoid arthritis.
Infusion process time
Infusion process times were significantly lower for GLM-IV (45.8 min) compared to IFX (134.1 min; p < .0001, ). The majority of infusion monitoring checks were reported as routine staff checks, such as checking patient vital signs (62.5% for GLM-IV and 80.8% for IFX; p = .0176). After adjusting for confounders, the least squares mean (SE) for total clinic personnel infusion process time remained significantly different (p < .0001) between GLM-IV (49.8 [3.5] min) and IFX (134.8 [2.9] min).
Treatment satisfaction
Patients
Significant differences in patient satisfaction, as reported on the TSQM-IV RA, between GLM-IV and IFX were observed for satisfaction with time to receive infusion (Q5: 6.3 for GLM-IV and 5.2 for IFX; p < .0001) and satisfaction with time from arrival at center to departure (Q6: 6.1 for GLM-IV and 5.5 for IFX; p = .0003). Significant differences were also noted in variables positively and negatively affecting satisfaction with the infusion process; length of infusion was identified as a significant factor across the treatment groups (Supplementary Figure), as a positive impact for 72.9% of GLM-IV and 36.4% of IFX patients (p < .0001), and as a negative impact for 2.9% of GLM-IV and 20.8% of IFX patients (p = .0008).
Other responses on the TSQM-IV RA showed patient reports of satisfaction to be similar for GLM-IV and IFX () with respect to the ability of infusion medication to treat RA (Q1), the way infusion medication relieves RA symptoms (Q2), the time from infusion to first relief of RA symptoms (Q3), the ease of scheduling infusion appointment (Q4), concern of side-effect from preventative medication (Q8), confidence that it is good to receive preventative medication prior to infusion (Q9), and satisfaction with total infusion experience and treatment of RA (Q10). No significant difference between the treatments was observed after adjusting for confounders.
Figure 2. Patient satisfaction (modified) TSQM-IV RA. A higher score indicates more satisfaction, ease, concern, or confidence (scale 1–7). (Q1) How satisfied or dissatisfied are you with the ability of the infusion medication to treat your RA? (Q2) How satisfied or dissatisfied are you with the way the infusion medication relieves your RA symptoms? (Q3) How satisfied or dissatisfied are you with the amount of time it takes the infusion medication to start working to relieve your RA? (Q4) How easy or difficult is it to schedule an appointment for your infusion? (Q5) How satisfied are you with the time it takes to receive your infusion? (p < .0001) (Q6) How satisfied are you with the time it takes from when you enter the infusion center until you can leave? (p = .0003) (Q8) How concerned are you about having a side-effect from the oral or intravenous preventative medication given just prior to the infusion? (Q9) Overall, based on your actual experience, how confident are you that taking this preventative medication just prior to infusion is a good thing for you? (Q10) With all things considered, how satisfied or dissatisfied are you with the total infusion experience and the treatment of your rheumatoid arthritis? Permission to use the TSQM-IV RA was provided by Quintiles.
*Question was asked only if patient received oral or IV medication prior to infusion. Responses: GLM-IV, n = 12; IFX, n = 54.Note: 3 patients did not complete the questionnaire; 2 for golimumab injection (IV) and 1 for infliximab.Abbreviations: GLM, golimumab; IFX, infliximab; IV, intravenous; RA, rheumatoid arthritis; TSQM-IV RA, Treatment Satisfaction Questionnaire for Medication-Intravenous RA, version 1.
Clinic personnel
Due to the small sample size for the clinic personnel data, no formal statistical comparisons were performed. Generally, GLM-IV received higher satisfaction scores from clinic personnel compared to IFX regarding the time to prepare the medication bag, ease of mixing RA medication, frequency of RA patients requiring pre-medication, and time needed for infusion ().
Figure 3. Clinic personnel satisfaction. Assessed by a Likert scale (0–10); a higher score indicates greater satisfaction. Q1: How satisfied are you with the time is takes to mix the RA medication into the infusion medication bag? Q2: How satisfied are you with the ease of mixing the RA medication? Q3: How satisfied are you with the frequency of RA medication patients requiring pre-medication? Q4: How satisfied are you with the amount of time it takes to infuse infliximab/golimumab injection (IV)?
Abbreviations: GLM, golimumab; IFX, infliximab; IV, intravenous; RA, rheumatoid arthritis.
Clinic personnel reported similar satisfaction for GLM-IV and IFX with respect to the process of storing vials (9.0 for GLM-IV and 8.8 for IFX), calculating RA medication dose (9.5 for GLM-IV and 9.4 for IFX), amount of time required for post-infusion monitoring of patients (9.4 for GLM-IV and 9.0 for IFX), and ease of scheduling patients (9.4 for GLM-IV and 9.3 for IFX). Clinic personnel were moderately satisfied with the ease of scheduling GLM-IV infusions on the same day as IFX infusions (7.4), the length of time to complete medical billing for both treatments (7.5), and satisfaction with benefit verifications for both treatments (5.7).
Adverse events
One adverse event was reported during the study. A 67-year old male patient treated with GLM-IV developed hives near the end of the infusion. The event resolved after administration of oral diphenhydramine.
Discussion
Summary of findings
In this real-world study, we assessed infusion times with GLM-IV and IFX for adult RA patients and factors associated with treatment satisfaction from the perspective of the patient and clinic personnel. Such a study is of importance given the limited published evidence summarizing the efficiency of RA biological therapies globally and in the USCitation11,Citation12, and the increased focus on gains in efficiency as a means for improving value in healthcare, a topic of focus by the Institute of Medicine and the Agency for Healthcare Quality and Research (AHRQ) over the last decadeCitation14. Various definitions and measures of efficiency in healthcare have been defined, but in its simplest terms efficiency can be defined as a measure of the greatest value for moneyCitation15. Palmer and TorgersonCitation15 further categorized healthcare efficiency into that which discriminates between value of resources required to produce superior health outcomes (technical efficiency), value of resources required to produce health outcomes that are presumed to be equivalent (productive efficiency), and allocative efficiency, which considers productive efficiency based upon the distribution of resources in a particular community which might now be known as “population health”.
In this study, we assume the perspective of productive efficiency between GLM-IV and IFX, since no head-to-head study demonstrating clinical superiority of one of these agents over the other was found in the published literature. Our findings showed that infusion time for RA medication and clinic duration time were more efficient for GLM-IV compared to IFX, although patient preparation times were similar between the treatment groups. Infusion time was the most significant contributor to the total duration and is, therefore, a critical differentiator in the efficiency of GLM-IV and IFX. For GLM-IV, mean total infusion time was 32.8 min, with the mean clinic visit duration lasting 65.1 min. For IFX, mean total infusion time was 119.1 min, with the mean clinic visit duration requiring 153.1 min. Likewise, product preparation time for GLM-IV was more efficient than IFX. The differences in product preparation time are not unexpected, since GLM-IV requires no reconstitution prior to dilution in the infusion bag, while IFX requires a separate reconstitution step prior to dilution in the infusion bag. Additionally, in this study, fewer vials per infusion were used for patients receiving GLM-IV than those treated with IFX, although the mean and median body weights were similar between the cohorts. The combination of patient body weight and physician prescribed weight-based dose of IFX can contribute to greater variations in the number of IFX vials required for reconstitution. In this study, the observed weight-based dose for IFX was higher than the minimum weight-based dose of IFX as given in the package insert, but still within the recommended dosing range of 3–10 mg/kg.
Although cost was not assessed in this study, the efficiency and cost of GLM-IV and IFX from the commercial reimbursement perspective using retrospective claims data in RA patients who were matched for a number of characteristics, including gender, payer type, prior biologic use, post-index methotrexate use, and duration of GLM-IV or IFX therapy, has been previously reportedCitation16. In that analysis, patients treated with IFX had overall higher drug plus administration costs over the first year of therapy, due to longer billed administration time, a greater number of vials per infusion, and a greater number of infusions per year as compared to GLM-IV. The differences in medication utilization resulted in an estimated annual cost savings of $10,507 for GLM-IV as compared to IFX.
Another important finding of this research is that patients treated with GLM-IV reported higher satisfaction than patients receiving IFX with respect to noted measures of efficiency between the two products. This is in specific reference to infusion time and total clinic visit time, even though patients in both groups were relatively equally satisfied with how the medications treated their RA, as suggested by other items of treatment satisfaction listed on the modified TSQM-IV. Furthermore, differences in efficiency of the two products were noted by clinic personnel, including higher satisfaction with GLM-IV preparation, ease of mixing, frequency of pre-medication administration, and overall infusion time as compared to IFX. Taken together, the finding of this study in combination with published data from related claims-based studies lend support to suggest GLM-IV as a more efficient product, with the potential to reduce cost and improve patient and healthcare professional satisfaction, compared to IFX. While this study was conducted prior to the introduction of biosimilar IFX, further investigations should examine overall differences between GLM-IV and biosimilar IFX in terms of efficiency and annual costs.
Limitations
As an observational study, no randomization was performed for the two treatment arms. However, even after adjusting for treatment differences, the primary time end-points were still significantly different from one another. This study assessed only one infusion per enrolled patient, and did not assess previous infusions to determine whether the infusion studied was representative of every infusion for that patient or whether the patient’s prior treatment history influenced responses to the study questionnaire. Further, the study results do not apply to patients who receive GLM by subcutaneous pen or syringe.
The study was not designed to assess relative value units associated with reimbursement and, as such, the findings are not generalizable to other disease states for costing purposes.
Observers on-site captured clinic personnel time spent on medication preparation, patient preparation, and personnel time during the course of a single infusion per patient. These findings may not be representative of care delivery for all infusion practices or for all patients. Observers received specific and detailed training on how to capture time-related variables, but small variations may have occurred across the six sites, as observers varied by site.
The TSQM-IV was used for the study prior to its validation within an RA patient population. While the questions appeared clear in context and relevant to this patient population, there is the possibility that some questions did not resonate. As with most patient-reported research, there was no opportunity to query patient data from completed questionnaires.
Conclusions
Administration of GLM-IV was associated with greater process efficiency compared to IFX, as noted by shorter overall clinic visit, infusion process, and RA medication infusion times. Infusion process time for each product was likely the primary driver for observed differences. Results of the patient questionnaires indicated a greater satisfaction for GLM-IV compared to IFX for infusion process time and total visit time. Clinic personnel reported higher satisfaction with GLM-IV preparation, ease of mixing, frequency of pre-medication administration, and overall infusion time as compared to IFX.
Transparency
Declaration of funding
Janssen Scientific Affairs, LLC sponsored the study, and Covance Market Access Services, Inc. received funding for the research and manuscript development.
Declaration of financial relationships
SRD and CL are employees of Covance Market Access Services, Inc. JDM was an employee of Covance Market Access Services, Inc. at the time of study conduct and development of the first manuscript draft. CP is an employee of The Resource Group. MZ is an employee of Janssen Biotechnology, Inc. LE is an employee of Janssen Scientific Affairs, LLC. MZ and LE are stockholders in Johnson and Johnson. Peer reviewers on this manuscript have received an honorarium from JME for their review work, but have no other relevant financial relationships to disclose.
Previous presentations
Data for this study were presented in part at the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research, May 20–24, 2017, in Boston, MA.
Supplemental material
Download MS Word (50.3 KB)Acknowledgments
The authors take full responsibility for the content of, and the decision to submit, this manuscript, but thank Teresa Oblak, PhD, CMPP, of Covance Market Access Services, Inc., for providing research and editorial support.
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