Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial.

OBJECTIVE: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. METHODS: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. RESULTS: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. CONCLUSIONS: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.

Self-monitoring combined with patient-initiated care in RA patients with low disease activity: cost-effectiveness analysis of an RCT.

OBJECTIVES: Self-monitoring and patient-initiated care (PIC) leads to fewer outpatient clinic visits in patients with established RA with low disease activity (LDA) while healthcare outcomes are similar. This study assesses the cost-effectiveness of PIC with self-monitoring. METHODS: A 12-month randomized controlled trial was performed with 49 patients in the PIC with self-monitoring group (app-group) and 53 in usual care. The usual care group continued with preplanned visits. The app group had one planned follow-up visit after 12 months and monitored their RA disease activity in a smartphone app. Both groups could make additional appointments at liberty. We included adult RA patients with a disease duration of over 2 years, a disease activity score 28 (DAS28) below 3.2 that were stable on medication for at least 6 months. The effect measure, the DAS28, was measured at 12 months and healthcare resource usage and productivity losses were measured at 3, 6, 9 and 12 months. RESULTS: There was no significant difference in mean change of DAS28 (-0.04 mean difference, 95% CI: -0.39, 0.30), nor a statistically significant difference in total costs (mean difference €514, 95% CI:-€266, €3690) in the app group compared with the usual care group. The probability that the app was cost-effective was 0.37 and 0.57 at a willingness-to-pay threshold of 0 and 50 000 €/point improvement DAS28, respectively. CONCLUSION: Although rheumatic care costs were significantly lower in the app group, total costs and effects of PIC with self-monitoring were not different from usual care in RA patients with LDA.

Facilitators and barriers to adhere to monitoring disease activity with ePROs: a focus group study in patients with inflammatory arthritis.

Telemonitoring disease activity with electronic patient-reported outcomes (ePROs) may reduce the workload of rheumatic care by decreasing outpatient clinic visits. However, low adherence to reporting ePROs is frequently observed. Our objective was to identify facilitators and barriers to weekly monitoring of disease activity with ePROs. Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) who recently participated in one of the two telemonitoring studies with ePROs completed in a smartphone app, were invited to participate in focus group discussions (FGD). Thematic analysis was used to identify themes that play a role in the decision to continue or stop reporting weekly ePROs. A total of 22 patients participated in three FGDs. Five themes were identified that were of importance to adhere to telemonitoring: (1) questionnaire frequency, (2) discussing results of completed ePROs, (3) physical consultations, (4) patient insight into disease activity and (5) user experience of the app. All themes contained both barrier and facilitator elements. The results suggest that to improve adherence to telemonitoring of disease activity with ePROs, the perceived benefits of completing ePROs should be maximized. This can be done by providing patients the ability to skip (unneeded) physical consultations in case of low disease activity, and training clinicians to always discuss the completed ePROs. In addition, it is essential to reduce the effort to report ePROs, by tailoring the frequency of ePROs based on the patients' disease activity or preference, aiming for optimal app functionality as well as by sending notifications when new ePROs are available.

Predictors for response to electronic patient-reported outcomes in routine care in patients with rheumatoid arthritis: a retrospective cohort study.

Routine collection of electronic patient-reported outcomes (ePROs) can improve clinical care. However, a low response rate may counteract the benefits. To optimize adoption, the aim of this study was to investigate which patient factors and/or timing of the invitation predicted response to ePROs sent prior to consultations in patients with rheumatoid arthritis. We performed a retrospective database study with clinical data collected as part of usual care from the electronic medical records at Reade Amsterdam. The dataset comprised the email invitations to complete the ePRO sent prior to consultation. Multiple patient factors and factors defining the timing of the invitation were investigated if they predicted response to the ePRO through a multivariable logistic generalized estimating equation analysis. In total, 17.070 ePRO invitations were sent to 3194 patients (mean age 60 (SD 14), 74% female), of which 40% was completed. Patients between 55 and 73 years (OR 1.39, 95%CI 1.09-1.77) and with higher social economic status (SES) (OR 1.51, 95%CI 1.22-1.88) had significantly higher odds for completing the ePRO, while patients living in an urban area had lower odds (OR 0.69, 95% CI 0.62-0.76). In year 4 after implementation, the OR was increased to 3.69 (95% CI 2.91-4.90). The implementation of ePROs in daily clinical practice needs improvement since 40% of the ePROs sent prior to consultations were completed. Patients that had higher odds to report the next ePRO were between the age of 55-73, had a higher socio-economic status, and were residents in a rural area. The adoption of reporting the PRO increased over time, but the timing of the prompt did not predict response. Additional research is needed to understand ePRO completion, especially for patients with lower socio-economic status.

Favourable effect of a 'second hit' after 13 weeks in early RA non-responders: the Amsterdam COBRA treat-to-target randomized trial.

OBJECTIVE: The aim of this study was to investigate the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA. METHODS: Early RA patients were classified as being at high or low risk of worsening RA based on disease activity and prognostic factors. High-risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, MTX increasing to 25 mg/week), and low-risk patients received MTX monotherapy increasing to 25 mg/week. The primary outcome (target) was DAS44 < 1.6 or EULAR good response at 26 weeks. At 13 weeks, non-responders were randomized to (open-label) intensification [high-risk patients: prednisolone 60 mg/day tapered to 7.5 mg/day, addition of SSZ (2 g/day) and HCQ (400 mg/day); low-risk patients: prednisolone 30 mg/day tapered to 7.5 mg/day] or continuation. RESULTS: In the high-risk group (n = 150), 110 patients (73%) reached the target at 13 weeks, and 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n = 16), and after 26 weeks, 12 (80%) vs 7 (44%) of these, respectively, reached the target [difference: 36%, (95% CI 2%, 71%); P = 0.04]. In the low-risk group (n = 40), 17 (43%) reached the target. Non-responders were randomized to intensification (n = 8) or continuation (n = 7); 4 vs 3, respectively, reached the target.Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup of that group. Serious adverse events were rare. Protocol violations were frequent and mostly led to mitigation of actual treatment intensification. CONCLUSION: Initial combination therapy was very successful in high-risk RA, and early intensification was beneficial in patients not reaching the strict target. The low-risk group was too small for drawing conclusions. In routine practice, adherence to early intensification based on strict targets is difficult. TRIAL REGISTRATION: Netherlands Trial Register (NTR), NL4393, https://www.trialregister.nl/.

Probability of Medication Intensifications in Rheumatoid Arthritis Patients With Low Disease Activity Scores on Their Patient-Reported Outcomes: A Medical-Records Review Study.

BACKGROUND: Patients with rheumatoid arthritis require frequent consultations to monitor disease activity and intensify medication when treatment targets are not met. However, because most patients are in remission during follow-up, it should be possible to reduce the number of consultations for them. Electronic patient-reported outcomes (ePROs) could be used to identify patients who meet their treatment goal and who could therefore be eligible to skip their visit. OBJECTIVE: The aim of this study was to assess the probability that patients with low disease activity scores on their ePROs do not need a disease-modifying antirheumatic drug (DMARD) or steroid intensification in the first 2 weeks after completion of the ePROs. METHODS: This medical-records review study compared results of ePROs answered during routine care with DMARD or steroid intensifications collected from anonymized electronic medical record at Reade. The primary outcome was the positive predictive value (PPV) of having a low disease activity score on an ePRO for not receiving a DMARD or steroid intensifications within 2 weeks. The 3 studied ePROs (and respective low disease activity outcome) were the Routine Assessment of Patient Index Data 3 (RAPID3) (score <2), Patient Acceptable Symptom State (PASS) (yes), and the flare question (no). The secondary aim of the study was to assess which combination of ePROs resulted in the best PPV for DMARD or steroid intensifications. RESULTS: Of the 400 randomly selected records, ultimately 321 were included (302 unique patients). The PPV of a RAPID3 <2, being in PASS, and a negative answer on the flare question were, respectively, 99%, 95%, and 83% to not receive a DMARD or steroid intensification within 2 weeks. The combination of a RAPID3 <2 and a negative flare question resulted in a PPV of 100%; this combination was present in 29% (93/321) of the total study population. CONCLUSION: The RAPID3, PASS, and flare question have a high diagnostic accuracy to identify individuals who will not receive a DMARD or steroid intensification in the following 2 weeks. The combination of the RAPID3 and flare question yielded the best combination of diagnostic accuracy and highest percentage of patients who could be eligible to skip a visit. These results suggest that accurate identification of patients who meet their treatment goal with ePROs is possible.

Smartphone-Assisted Patient-Initiated Care Versus Usual Care in Patients With Rheumatoid Arthritis and Low Disease Activity: A Randomized Controlled Trial.

OBJECTIVE: We developed a smartphone application for patients with rheumatoid arthritis (RA) that allows them to self-monitor their disease activity in between clinic visits by answering a weekly Routine Assessment of Patient Index Data 3. This study was undertaken to assess the safety (noninferiority in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR]) and efficacy (reduction in number of visits) of patient-initiated care assisted using a smartphone app, compared to usual care. METHODS: A 12-month, randomized, noninferiority clinical trial was conducted in RA patients with low disease activity and without treatment changes in the past 6 months. Patients were randomized 1:1 to either app-supported patient-initiated care with a scheduled follow-up consultation after a year (app intervention group) or usual care. The coprimary outcome measures were noninferiority in terms of change in DAS28-ESR score after 12 months and the ratio of the mean number of consultations with rheumatologists between the groups. The noninferiority limit was 0.5 difference in DAS28-ESR between the groups. RESULTS: Of the 103 randomized patients, 102 completed the study. After a year, noninferiority in terms of the DAS28-ESR score was established, as the 95% confidence interval (95% CI) of the mean ΔDAS28-ESR between the groups was within the noninferiority limit: -0.04 in favor of the app intervention group (95% CI -0.39, 0.30). The number of rheumatologist consultations was significantly lower in the app intervention group compared to the usual care group (mean ± SD 1.7 ± 1.8 versus 2.8 ± 1.4; visit ratio 0.62 [95% CI 0.47, 0.81]). CONCLUSION: Patient-initiated care supported by smartphone self-monitoring was noninferior to usual care in terms of the ΔDAS28-ESR and led to a 38% reduction in rheumatologist consultations in RA patients with stable low disease activity.

The Prognostic Accuracy of Clinical Judgment Versus a Validated Frailty Screening Instrument in Older Patients at the Emergency Department: Findings of the AmsterGEM Study.

STUDY OBJECTIVE: To compare the prognostic accuracy of clinical judgment for frailty in older patients at the emergency department with a validated screening instrument and patient-perceived frailty. METHODS: A prospective cohort study in patients 70 years of age and older in 2 Dutch EDs with a follow-up of 3 months. A dichotomous question was asked to the physician and patient: "Do you consider the patient / yourself to be frail?" The Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) was used as a validated screening instrument. The primary composite outcome consisted of either functional decline, institutionalization, or mortality. RESULTS: A total of 736 patients were included. The physician identified 59% as frail, compared with 49% by ISAR-HP and 43% by patients themselves. The level of agreement was fair (Fleiss Kappa, 0.31). After 3 months, 31% of the patients experienced at least 1 adverse health outcome. The sensitivity was 79% for the physician, 72% for ISAR-HP, 61% for the patient, and 48% for all 3 combined. The specificity was 50% for the physician, 63% for ISAR-HP, 66% for the patient, and 85% for all 3 positive. The highest positive likelihood ratio was 3.03 (physician, ISAR-HP, patient combined), and the lowest negative likelihood ratio was 0.42 (physician). The areas under the receiver operating curves were all poor: 0.68 at best for ISAR-HP. CONCLUSION: Clinical judgment for frailty showed fair agreement with a validated screening instrument and patient-perceived frailty. All 3 instruments have poor prognostic accuracy, which does not improve when combined. These findings illustrate the limited prognostic value of clinical judgment as a frailty screener in older patients at the ED.

Great saves or near misses? Severe maternal outcome in Metro East, South Africa: A region-wide population-based case-control study.

OBJECTIVE: To assess the incidence of severe maternal outcome (SMO), comprising maternal mortality (MM) and maternal near miss (MNM), in Metro East health district, Western Cape Province, South Africa between November 2014 and November 2015 and to identify associated determinants leading to SMO with the aim to improve maternity care. METHODS: Region-wide population-based case-control study. Women were included in the study, if they were maternal deaths or met MNM criteria, both as defined by WHO. Characteristics of women with SMO were compared with those of a sample of women without SMO, matched for age and parity, taken from midwifery-led obstetrical units from two residential areas in Metro East, using multivariate regression analysis. RESULTS: Incidence of SMO was 9.1 per 1000 live births, and incidence of MNM was 8.6 per 1000 live births. Main causes of SMO were obstetrical hemorrhage and hypertensive disorders. Factors associated with SMO were HIV (adjusted odds ratio [aOR] 24.8; 95% confidence interval [CI] 10.0-61.6), pre-eclampsia (aOR 17.5; 95% CI 7.9-38.7), birth by cesarean section (aOR 8.4; 95% CI 5.8-12.3), and chronic hypertension (aOR 2.4; 95% CI 1.1-5.1). CONCLUSION: Evaluation of SMO incidence and associated determinants supports optimizing tailored guidelines in Metro-East health district to improve maternal health.

Work participation in patients with systematic lupus erythematosus: a systematic review.

OBJECTIVES: This systematic review assessed which variables are associated with or are predictors for work participation outcomes in patients with systematic lupus erythematosus (SLE). METHODS: A literature search using MEDLINE, The Cochrane Library, Embase and CINAHL was conducted to identify all studies published from inception (1947) to June 2021 on factors related to and/or predicting employment status, absenteeism and/or presenteeism in SLE patients aged ≥18 years. The quality of included articles was assessed using the QUIPS tool. Narrative summaries were used to present the data. RESULTS: Fifteen studies (nine on associations, four on predictions, and two assessing both) were included, encompassing data of 3800 employed patients. Younger age, Caucasian ethnicity, higher educational level, lower disease activity score, shorter disease duration, absence of specific disease manifestations, higher levels of physical functioning and less physical job demands and higher levels of psychological/cognitive functioning were associated with or predicted favorable work outcomes. Older age, non-Caucasian ethnicity, female gender, never being married, poverty, lower educational level, higher disease activity score, longer disease duration, specific disease manifestations, lower levels of physical functioning, more physical job demands and low job control, less job tenure and lower levels of cognitive functioning were associated with or predicted an unfavorable work outcome. Limitations of the evidence were the quality of the studies and the use of heterogeneous outcome measures, applied statistical methods and instruments used to assess work participation. CONCLUSION: We recommend applying the EULAR points to consider for designing, analysing and reporting on work participation in inflammatory arthritis also to SLE studies on work participation, to enhance the quality and comparability between studies and to better understand the impact of SLE on work participation. TRIAL REGISTRATION: registration in PROSPERO (CRD42020161275; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=161275).

The Accuracy of Four Frequently Used Frailty Instruments for the Prediction of Adverse Health Outcomes Among Older Adults at Two Dutch Emergency Departments: Findings of the AmsterGEM Study.

STUDY OBJECTIVE: Older adults presenting to the emergency department (ED) are at high risk of adverse health outcomes. This study aimed to evaluate the accuracy of 4 frequently used screening instruments for the prediction of adverse health outcomes among older adults in the ED. METHODS: This was a prospective cohort study in patients ≥70 years of age presenting to the ED in 2 hospitals in the Netherlands. Screening instruments included the acutely presenting older patient screening program (APOP) (providing 2 risk scores-functional decline [APOP1] and mortality [APOP2]), the International Resident Assessment Instrument Emergendy Department screener (InterRAI ED), the Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP), and the safety management system (VMS). The primary outcome measure was a composite outcome encompassing functional decline, institutionalization, and mortality at 3 months after ED presentation. Other follow-up time points were 1 and 6 months. Analyses were performed to assess prognostic accuracy. RESULTS: In total, 889 patients were included. After 3 months, 267 (31%) patients experienced at least 1 adverse outcome. The positive likelihood ratio ranged from 1.67 (VMS) to 3.33 (APOP1), and the negative likelihood ratio ranged from 0.41 (ISAR-HP) to 0.88 (APOP2). Sensitivity ranged from 17% (APOP2) to 74% (ISAR-HP), and specificity ranged from 63% (ISAR-HP) to 94% (APOP2). The area under the curve ranged from 0.62 (APOP2) to 0.72 (APOP1 and ISAR-HP). Calibration was reasonable for APOP1 and VMS. The prognostic accuracy was comparable across all outcomes and at all follow-up time points. CONCLUSION: The frailty screening instruments assessed in this study showed poor to moderate prognostic accuracy, which brings into question their usability in the prediction of adverse health outcomes among older adults who present to the ED.

EULAR Points to Consider (PtC) for designing, analysing and reporting of studies with work participation as an outcome domain in patients with inflammatory arthritis.

BACKGROUND: Clinical studies with work participation (WP) as an outcome domain pose particular methodological challenges that hamper interpretation, comparison between studies and meta-analyses. OBJECTIVES: To develop Points to Consider (PtC) for design, analysis and reporting of studies of patients with inflammatory arthritis that include WP as a primary or secondary outcome domain. METHODS: The EULAR Standardised Operating Procedures were followed. A multidisciplinary taskforce with 22 experts including patients with rheumatic diseases, from 10 EULAR countries and Canada, identified methodologic areas of concern. Two systematic literature reviews (SLR) appraised the methodology across these areas. In parallel, two surveys among professional societies and experts outside the taskforce sought for additional methodological areas or existing conducting/reporting recommendations. The taskforce formulated the PtC after presentation of the SLRs and survey results, and discussion. Consensus was obtained through informal voting, with levels of agreement obtained anonymously. RESULTS: Two overarching principles and nine PtC were formulated. The taskforce recommends to align the work-related study objective to the design, duration, and outcome domains/measurement instruments of the study (PtC: 1-3); to identify contextual factors upfront and account for them in analyses (PtC: 4); to account for interdependence of different work outcome domains and for changes in work status over time (PtC: 5-7); to present results as means as well as proportions of patients reaching predefined meaningful categories (PtC: 8) and to explicitly report volumes of productivity loss when costs are an outcome (PtC:9). CONCLUSION: Adherence to these EULAR PtC will improve the methodological quality of studies evaluating WP.

How to enhance recruitment of individuals at risk of rheumatoid arthritis into trials aimed at prevention: understanding the barriers and facilitators.

OBJECTIVES: Several trials to test the efficacy of a pharmacological intervention aimed at primary prevention of rheumatoid arthritis (RA) are ongoing or have recently been completed. A common issue in these trials is the severe difficulty with patient recruitment. In order to enhance recruitment, this qualitative study identified barriers and facilitators of individuals at risk of RA to participate in a prevention trial. METHODS: Individuals at risk of developing RA (ie, arthralgia with anticitrullinated protein antibodies and/or rheumatoid factor without arthritis), who had previously been asked to participate in a prevention trial, participated in focus group discussions (n=18) exploring their facilitators and barriers for trial participation. Thematic analysis identified factors that were important in at-risk individuals' decision about trial participation. RESULTS: The prospect of personal benefit, the acknowledgement of one's symptoms and the desire to contribute to society facilitated trial participation. In contrast, misconception about what it means to be at risk, or about the aim of the prevention trial, negative views on trial medication, and a low perceived urgency to act on the possibility of developing RA versus a high perceived burden of participating in a trial discouraged participation. CONCLUSIONS: To enhance inclusion in trials aimed to prevent RA, the results suggest to use strategies such as optimising education about RA, personal risk, trial aim and trial medication, explicitly addressing misconceptions and concerns, using tools to improve information provision, limiting study burden in trial design and encouraging physicians to mention trial participation.

Methodological aspects of design, analysis and reporting of studies with work participation as an outcome domain in patients with inflammatory arthritis: results of two systematic literature reviews informing EULAR points to consider.

OBJECTIVE: To summarise the methodological aspects in studies with work participation (WP) as outcome domain in inflammatory arthritis (IA) and other chronic diseases. METHODS: Two systematic literature reviews (SLRs) were conducted in key electronic databases (2014-2019): search 1 focused on longitudinal prospective studies in IA and search 2 on SLRs in other chronic diseases. Two reviewers independently identified eligible studies and extracted data covering pre-defined methodological areas. RESULTS: In total, 58 studies in IA (22 randomised controlled trials, 36 longitudinal observational studies) and 24 SLRs in other chronic diseases were included. WP was the primary outcome in 26/58 (45%) studies. The methodological aspects least accounted for in IA studies were as follows (proportions of studies positively adhering to the topic are shown): aligning the studied population (16/58 (28%)) and sample size calculation (8/58 (14%)) with the work-related study objective; attribution of WP to overall health (28/58 (48%)); accounting for skewness of presenteeism/sick leave (10/52 (19%)); accounting for work-related contextual factors (25/58 (43%)); reporting attrition and its reasons (1/58 (2%)); reporting both aggregated results and proportions of individuals reaching predefined meaningful change or state (11/58 (16%)). SLRs in other chronic diseases confirmed heterogeneity and methodological flaws identified in IA studies without identifying new issues. CONCLUSION: High methodological heterogeneity was observed in studies with WP as outcome domain. Consensus around various methodological aspects specific to WP studies is needed to improve quality of future studies. This review informs the EULAR Points to Consider for conducting and reporting studies with WP as an outcome in IA.

Association of altered folylpolyglutamate synthetase pre-mRNA splicing with methotrexate unresponsiveness in early rheumatoid arthritis.

OBJECTIVES: An efficient pharmacological response to MTX treatment in RA patients relies on the retention and accumulation of intracellular MTX-polyglutamates catalysed by the enzyme folylpolyglutamate synthetase (FPGS). We recently identified a partial retention of FPGS intron 8 (8PR) as a prominent splice variant conferring FPGS dysfunction and decreased MTX polyglutamylation in acute lymphoblastic leukaemia. Here, we explored the association between FPGS 8PR levels and lack of MTX responsiveness in RA patients. METHODS: Thirty-six patients undergoing MTX treatment were enrolled from the Combinatie behandeling Reumatoide Artritis (COBRA)-light trial. RNA was isolated from blood samples at baseline, 13 weeks and 26 weeks of therapy, from patients in either COBRA-light (n = 21) or COBRA (n = 15) treatment arms. RT-qPCR analysis was used to assess RNA levels of FPGS 8PR over wild-type FPGS (8WT). RESULTS: In the COBRA-light treatment arm, higher baseline ratios of 8PR/8WT were significantly associated with higher 44-joint disease activity score (DAS44) at 13 and 26 weeks. Higher baseline ratios of 8PR/8WT also trended towards not obtaining low disease activity (DAS <1.6) and becoming a EULAR non-responder at 13 and 26 weeks. In the COBRA-treatment arm, a significant association was observed between high baseline 8PR/8WT ratios and higher DAS44 score at 26 weeks. Higher 8PR/8WT ratios were associated with non-response at week 26 based on both low disease activity and EULAR criteria. CONCLUSION: This study is the first to associate alterations in FPGS pre-mRNA splicing levels with reduced responsiveness to MTX treatment in RA patients. TRIAL REGISTRATION: ISRCTN55552928.

Intention-to-treat analysis when only a baseline value is available.

OBJECTIVES: How to perform an intention to treat (ITT) analysis when a patient has a baseline value but no follow-up measurements is problematic. The purpose of this study was to compare different methods that deal with this problem, i.e. no imputation (standard and alternative mixed model analysis), single imputation (i.e. baseline value carried forward), and multiple imputation (selective and non-selective). STUDY DESIGN AND SETTING: We used a simulation study with different scenarios regarding 1) the association between missingness and the baseline value, 2) whether the patients did or did not receive the treatment, and 3) the percentage of missing data, and two real life data sets. RESULTS: Bias and coverage were comparable between the two mixed model analyses and multiple imputation in most situations including the real life data examples. Only in the situation when the patients in the treatment group were simulated not to have received the treatment, selective imputation using this information outperformed all other methods. CONCLUSIONS: In most situations a standard mixed model analysis without imputation is appropriate as ITT analysis. However, when patients with missing follow-up data allocated to the treatment group did not received treatment, it is advised to use selective imputation, using this information, although the results should be interpreted with caution.

Asynchronous mHealth Interventions in Rheumatoid Arthritis: Systematic Scoping Review.

BACKGROUND: Mobile devices such as smartphones and tablets have surged in popularity in recent years, generating numerous possibilities for their use in health care as mobile health (mHealth) tools. One advantage of mHealth is that it can be provided asynchronously, signifying that health care providers and patients are not communicating in real time. The integration of asynchronous mHealth into daily clinical practice might therefore help to make health care more efficient for patients with rheumatoid arthritis (RA). The benefits have been reviewed in various medical conditions, such as diabetes and asthma, with promising results. However, to date, it is unclear what evidence exists for the use of asynchronous mHealth in the field of RA. OBJECTIVE: The objective of this study was to map the different asynchronous mHealth interventions tested in clinical trials in patients with RA and to summarize the effects of the interventions. METHODS: A systematic search of Pubmed, Scopus, Cochrane, and PsycINFO was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies were initially screened and later assessed by two independent researchers. Disagreements on inclusion or exclusion of studies were resolved by discussion. RESULTS: The literature search yielded 1752 abstracts. After deduplication and screening, 10 controlled intervention studies were included. All studies were assessed to be at risk for bias in at least one domain of the Cochrane risk-of-bias tool. In the 10 selected studies, 4 different types of mHealth interventions were used: SMS reminders (to increase medication adherence or physical activity; n=3), web apps (for disease monitoring and/or to provide medical information; n=5), smartphone apps (for disease monitoring; n=1), and pedometers (to increase and track steps; n=1). Measured outcomes varied widely between studies; improvements were seen in terms of medication compliance (SMS reminders), reaching rapid remission (web app), various domains of physical activity (pedometer, SMS reminders, and web apps), patient-physician interaction (web apps), and self-efficacy (smartphone app). CONCLUSIONS: SMS reminders, web apps, smartphone apps, and pedometers have been evaluated in intervention studies in patients with RA. These interventions have been used to monitor patients or to support them in their health behavior. The use of asynchronous mHealth led to desirable outcomes in nearly all studies. However, since all studies were at risk of bias and methods used were very heterogeneous, high-quality research is warranted to corroborate these promising results.

Patients' and rheumatologists' perceptions on preventive intervention in rheumatoid arthritis and axial spondyloarthritis.

BACKGROUND: Individuals at risk of developing rheumatoid arthritis (RA) may benefit from lifestyle or pharmacological interventions aimed at primary prevention. The same may apply to individuals at risk of axial spondyloarthritis (axSpA). Our aim was to investigate and compare the willingness of individuals at risk of RA or axSpA and rheumatologists to initiate preventive intervention. METHODS: Individuals at risk of RA (arthralgia and anti-citrullinated protein antibodies and/or rheumatoid factor positivity without arthritis (RA-risk cohort; n = 100)), axSpA (first-degree relatives of HLA-B27-positive axSpA patients (SpA-risk cohort; n = 38)), and Dutch rheumatologists (n = 49) completed a survey on preventive intervention which included questions about disease perception, lifestyle intervention, and preventive medication. RESULTS: At-risk individuals reported willingness to change median 7 of 13 lifestyle components in the areas of smoking, diet, and exercise. In contrast, 35% of rheumatologists gave lifestyle advice to ≥ 50% of at-risk patients. The willingness to use 100% effective preventive medication without side effects was 53% (RA-risk), 55% (SpA-risk), and 74% (rheumatologists) at 30% disease risk which increased to 69% (RA-risk) and 92% (SpA-risk and rheumatologists) at 70% risk. With minor side effects, willingness was 26%, 29%, and 31% (at 30% risk) versus 40%, 66%, and 76% (at 70% risk), respectively. CONCLUSIONS: Risk perception and willingness to start preventive intervention were largely similar between individuals at risk of RA and axSpA. Although the willingness to change lifestyle is high among at-risk individuals, most rheumatologists do not advise them to change their lifestyle. In contrast, rheumatologists are more willing than at-risk patients to start preventive medication.

Long-term sickness absence in a working population: development and validation of a risk prediction model in a large Dutch prospective cohort.

BACKGROUND: Societal expenditures on work-disability benefits is high in most Western countries. As a precursor of long-term work restrictions, long-term sickness absence (LTSA) is under continuous attention of policy makers. Different healthcare professionals can play a role in identification of persons at risk of LTSA but are not well trained. A risk prediction model can support risk stratification to initiate preventative interventions. Unfortunately, current models lack generalizability or do not include a comprehensive set of potential predictors for LTSA. This study is set out to develop and validate a multivariable risk prediction model for LTSA in the coming year in a working population aged 45-64 years. METHODS: Data from 11,221 working persons included in the prospective Study on Transitions in Employment, Ability and Motivation (STREAM) conducted in the Netherlands were used to develop a multivariable risk prediction model for LTSA lasting ≥28 accumulated working days in the coming year. Missing data were imputed using multiple imputation. A full statistical model including 27 pre-selected predictors was reduced to a practical model using backward stepwise elimination in a logistic regression analysis across all imputed datasets. Predictive performance of the final model was evaluated using the Area Under the Curve (AUC), calibration plots and the Hosmer-Lemeshow (H&L) test. External validation was performed in a second cohort of 5604 newly recruited working persons. RESULTS: Eleven variables in the final model predicted LTSA: older age, female gender, lower level of education, poor self-rated physical health, low weekly physical activity, high self-rated physical job load, knowledge and skills not matching the job, high number of major life events in the previous year, poor self-rated work ability, high number of sickness absence days in the previous year and being self-employed. The model showed good discrimination (AUC 0.76 (interquartile range 0.75-0.76)) and good calibration in the external validation cohort (H&L test: p = 0.41). CONCLUSIONS: This multivariable risk prediction model distinguishes well between older workers with high- and low-risk for LTSA in the coming year. Being easy to administer, it can support healthcare professionals in determining which persons should be targeted for tailored preventative interventions.

A Smartphone App for Self-Monitoring of Rheumatoid Arthritis Disease Activity to Assist Patient-Initiated Care: Protocol for a Randomized Controlled Trial.

BACKGROUND: Telemedicine based on self-measurement of disease activity could be one of the key components to create the health care system of the future. Previous publications in various medical fields have shown that it is possible to safely telemonitor patients while reducing the number of outpatient clinic visits. For this purpose, we developed a mobile phone app for patients with rheumatoid arthritis (RA), which allows them to self-monitor their disease. OBJECTIVE: The objective of this study is to assess the safety and efficacy of self-initiated care assisted by a smartphone app in patients with RA. METHODS: This is a randomized controlled trial that will be performed for 1 year. A total of 176 patients with RA will be randomized to either self-initiated care with only one scheduled follow-up consultation assisted by our app or usual care. The coprimary outcome measures are the number of outpatient clinic consultations with a rheumatologist taking place during the trial period and the mean disease activity score as measured by the disease activity score 28 (DAS28) at 12 months. The secondary outcomes are patient satisfaction, adherence, patient empowerment, and cost evaluation of health care assisted by the app. RESULTS: Recruitment started in May 2019, and up to 18 months will be required for completion of recruitment. Thus far, 78 patients have been randomized, and thus far, experiences with the app have been positive. The study results are expected to be published by the end of 2021. CONCLUSIONS: The completion of this study will provide important data regarding the following: (1) safety of self-initiated care supported by a smartphone app in terms of DAS28 and (2) efficacy of lowering health care usage with this new strategy of providing health care. TRIAL REGISTRATION: Netherlands Trial Register NL7715; https://www.trialregister.nl/trial/7715. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15105.