Feasibility of Self-Monitoring Rheumatoid Arthritis With a Smartphone App: Results of Two Mixed-Methods Pilot Studies.

BACKGROUND: Several mobile apps that monitor symptoms of rheumatoid arthritis (RA) exist, but a recent systematic review indicated that high-quality apps are lacking. When patients self-monitor their own disease with patient-reported outcomes (PROs) and self-initiate care at the right moment, it may be possible to reduce the frequency of their clinic visits, which would reduce health care burden and costs. We developed an app, that is, the MijnReuma Reade app, for this purpose and performed 2 pilot tests with weekly self-monitoring. OBJECTIVE: The primary objective of this study was to design, develop, and evaluate the usability, satisfaction, and usage of the MijnReuma Reade app-an app that allows patients with RA to monitor their own disease. The secondary objective was to review the patients' perspectives on app usage and its intended purpose. METHODS: This app was designed in collaboration with patients with RA, rheumatologists, and information technology experts. Two 1-month pilot studies were performed, after which satisfaction (0-10 scale), usability (system usability scale, 0-100), and usage (proportion of completed questionnaires) of this app were assessed. After the second pilot study, semistructured interviews were performed to determine patients' perspectives and the promoters and barriers of app usage. RESULTS: In the first and second pilot study, 42 and 27 patients were included, respectively. Overall, the patients were satisfied (medians, 8 and 7) and found the app usable (mean system usability scores, 76 and 71) in pilot studies 1 and 2, respectively. App usage declined over time in both the pilot studies; 61% (17/28) and 37% (10/27) of the patients who disclosed their usage statistics completed the final weekly questionnaire in pilot study 1 and pilot study 2, respectively. Approximately 81% (25/31) of the patients indicated they would like to skip hospital visits if the self-monitored disease activity is low. In the semistructured interviews, technical problems, internal resistance (respondent fatigue, the app reminded them of their disease), and a lack of symptoms were identified as barriers for usage. Patients reported that "experiencing more grip on their disease" and "improved communication with their physician" were promoters for usage. Patients reported that pain positively mediated usage, that is, more pain promoted and less pain discouraged app usage. CONCLUSIONS: This study illustrates the feasibility of the MijnReuma Reade app that enables self-monitoring of the disease activity in patients with RA with the overarching aim to allocate clinical consultations according to need. Satisfaction with the app and usability of the app were found to be high; however, app usage declined over time. Patients acknowledged the potential of the app to self-monitor their own disease and would like to be able to skip clinic visits if the monitored disease activity is low. To evaluate this strategy, a randomized controlled trial is underway.

Evaluation of dose-tapering strategies for intravenous tocilizumab in rheumatoid arthritis patients using model-based pharmacokinetic/pharmacodynamic simulations.

PURPOSE: Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones. METHODS: Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity. RESULTS: The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively). CONCLUSION: We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.

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.

The effect of methotrexate on tumour necrosis factor concentrations in etanercept-treated rheumatoid arthritis patients.

OBJECTIVES: Recently, we demonstrated that early low concentrations of circulating, adalimumab-bound TNF in RA patients treated with adalimumab was associated with future anti-drug antibody formation. Furthermore, low TNF was associated with less frequent baseline MTX use. This is remarkable, because of the anti-inflammatory effects of MTX and a potential inhibiting effect on cytokine production. We hypothesized an indirect effect of non-MTX use on low TNF concentrations via immunogenicity. To investigate the effect of MTX on TNF concentrations independent of anti-drug antibody formation, we measured TNF in RA patients treated with etanercept, a drug with low immunogenicity. METHODS: TNF was quantified in 186 consecutive etanercept-treated RA patients at baseline and at weeks 4, 16 and 28. The dynamics of TNF during etanercept treatment were compared with dynamics recently published for adalimumab. RESULTS: We demonstrated that TNF concentrations at week 4 did not associate with baseline MTX or remission after 28 weeks. Furthermore, median (interquartile range) TNF increased from <112 (<112-<112) pg/ml at baseline to 548 (344-688) pg/ml at week 4 and remained stable at week 16 and 28 [598 (442-756) and 568 (444-755) pg/ml, respectively]. CONCLUSION: Circulating TNF did not associate with MTX usage in etanercept-treated patients. This implies that MTX does not have a direct effect on TNF concentrations in circulation and that the association between early low TNF and non-use of MTX for adalimumab is thus most likely due to anti-drug antibody formation.

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.

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay.

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a "drug-tolerant" assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.

Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial.

OBJECTIVE: High adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity. METHODS: Consecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations >8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points. RESULTS: In total, 147 patients were screened. Fifty-five patients had concentrations >8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was -0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01). CONCLUSIONS: Adalimumab-treated patients with RA with trough concentrations >8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control. TRIAL REGISTRATION NUMBER: NTR3509; Results.

Long-term treatment response in rheumatoid arthritis patients starting adalimumab or etanercept with or without concomitant methotrexate.

OBJECTIVES: To observe long-term clinical response and drug survival in a prospective two-year cohort study in rheumatoid arthritis (RA) patients starting adalimumab or etanercept treatment, with or without methotrexate (MTX), after failure of conventional DMARD therapy, including MTX. METHODS: Disease activity score of 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were collected of 873 consecutive RA patients, treated with adalimumab or etanercept, prospectively at baseline, 4, 16, 28, 40, 52, 78 and 104 weeks of biological therapy. Sustained minimal disease activity (MDA), DAS28 <2.6 for at least 24 consecutive weeks, biological discontinuation, ΔHAQ and ΔDAS28 were compared between patients treated with or without concomitant MTX for etanercept and adalimumab separately. RESULTS: More patients treated with adalimumab and MTX (42%) achieved sustained MDA than patients without MTX (18%). The hazard ratio (HR) was 2.3 [1.4-3.9]. No significant difference was found in etanercept treatment (with MTX 33% vs. 28% without MTX), HR 1.1 [0.8-1.6]. More patients treated without MTX discontinued treatment than patients with MTX co-treatment in adalimumab (HR 2.1 [1.5-3.0]) and etanercept (HR 1.9 [1.0-3.4]). The mean decrease in DAS28 over time was higher for patients treated with MTX in adalimumab (regression coefficient (RC): 0.57, p<0.001), but was not significantly different in etanercept treatment (RC 0.05, p=0.427). No significant differences were found in ΔHAQ. CONCLUSIONS: Treatment discontinuation is lower in patients treated with MTX in both adalimumab and etanercept treatment. However, considering good clinical response, in contrast to etanercept, a synergetic effect of MTX is observed only in adalimumab treatment.