Abstract Background Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical ...response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). Methods Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA ( n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein JADAS27-CRP) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. Results At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio OR: 2.54 95% confidence interval (CI): 1.25–5.18), JIA-ACR100 (OR: 3.72 95% CI: 1.48–9.37), JIA-ACR inactive disease (ID; OR: 4.25 95% CI: 2.03–8.92), JADAS27-CRP ID (OR: 2.34 95% CI: 1.02–5.39) at month 4, and JIA-ACR ID (OR: 3.01 95% CI: 1.57–5.78) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 95% CI: 1.23–5.13), JIA-ACR100 (OR: 3.68 95% CI: 1.46–9.28), JIA-ACR ID (OR: 3.66 95% CI: 1.76–7.61), JIA-ACR90 (OR: 2.03 95% CI: 1.07–3.87), JIA-ACR100 (OR: 2.14 95% CI: 1.10–4.17), and JIA-ACR ID (OR: 4.22 95% CI: 2.15–8.29) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. Conclusion Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
To investigate the frequency and trajectories of individual patients with polyarticular-course juvenile idiopathic arthritis (JIA) achieving novel composite end points on abatacept.
Data from a ...clinical trial of subcutaneous abatacept (NCT01844518) and a post hoc analysis of intravenous abatacept (NCT00095173) in patients with polyarticular-course JIA were included. Three end points were defined and evaluated: combined occurrence of low disease activity (LDA) measured by the Juvenile Arthritis Disease Activity Score; 50% improvement in American College of Rheumatology criteria for JIA (ACR50); and patient-reported outcomes. Patient-reported outcomes included visual analog scale score of minimal pain (pain-min) and Childhood Health Assessment Questionnaire disability index score of 0 (C-HAQ DI0). In this post hoc analysis, maintenance of month 13 and 21 end points (LDA+pain-min, LDA+C-HAQ DI0, and ACR50+pain-min) in those who achieved them at month 4 was determined.
Composite end points (LDA+pain-min, LDA+C-HAQ DI0, and ACR50+pain-min) were achieved at month 4 (44.7%, 19.6%, and 58.9% of the 219 patients treated with subcutaneous abatacept, respectively). Of those who achieved LDA+pain-min at month 4, 84.7% (83 of 98) and 65.3% (64 of 98) maintained LDA+pain-min at months 13 and 21, respectively. The proportions of patients meeting LDA+pain-min outcomes increased from 44.7% (98 of 219) at month 4 to 54.8% (120 of 219) at month 21. The frequency of patients who met an LDA+C-HAQ DI score of 0 increased from 19.6% (43 of 219) at month 4 to 28.8% (63 of 219) at month 21.
Among individual patients with polyarticular-course JIA treated with abatacept who achieved 1 of the combined clinical and patient-reported outcomes composite end points, many maintained them over 21 months of abatacept treatment.
ObjectiveThis report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA).MethodsIn this ...three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0–16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16–48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety.ResultsAmong 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA.ConclusionAlthough the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred.Clinical Trial RegistrationNCT01230827; Results.
Objective
To document the need for additional Food and Drug Administration (FDA)–approved medications for the treatment of juvenile idiopathic arthritis (JIA).
Methods
The electronic medical records ...of JIA patients treated at Cincinnati Children's Hospital Medical Center (CCHMC) and data from JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry were included in this study. Unmet medication need was defined in 2 ways: (a) the presence of chronically uncontrolled JIA, defined as a physician global assessment of JIA activity ≥3 (on a 0–10 scale, where 0 = inactive) OR ≥3 joints with active arthritis OR a patient global assessment of well‐being ≥3 (on a 0–10 scale, where 0 = very well), despite sequential use of ≥2 biologic disease‐modifying antirheumatic drugs (bDMARDs); and (b) the use of ≥1 bDMARD not approved for any JIA category.
Results
At CCHMC, 829 of 1,599 JIA patients (52%) were treated with ≥1 bDMARD, and 304 (19%) had been exposed to ≥1 unapproved bDMARD. In the CARRA Registry, 4,766 of 7,379 children (65%) had received ≥1 bDMARD, and 1,122 (15%) had been prescribed ≥1 unapproved bDMARD. Of those children treated with ≥2 bDMARDs for whom complete data were available, 52% (255 of 487) at CCHMC and 45% (527 of 1,159) in the CARRA Registry had chronically uncontrolled JIA despite the use of ≥2 bDMARDs.
Conclusion
Despite the availability of bDMARDs currently approved for JIA, there is persistent need for additional therapies to control JIA signs and symptoms. Since FDA approval is critical to ensure access to bDMARDs, the study and licensing of new medications is critical to address the unmet medication need and to further improve JIA outcomes.
Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and ...taste acceptability of tofacitinib in patients with JIA.
This Phase 1, open-label, multiple-dose (twice daily BID for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated.
Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUC
) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; C
(ng/mL) was 47.0, 41.7, and 66.2, respectively. C
, C
, and t
were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to C
(T
) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed.
PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program.
ClinicalTrials.gov: NCT01513902 .
Specialized research networks are essential to achieve drug approvals for rare pediatric diseases. Such networks help realize the potential of global legislation enacted upon the recognition that ...most children are treated with drugs whose most beneficial dose and regimen have not been established in pediatric patients. The Pediatric Rheumatology Collaborative Study Group (PRCSG) is a North American clinical trials network that is specialized in the performance of clinical trials of new therapies for pediatric populations with rheumatic diseases. This review provides an overview of the strategies employed by this research network to achieve drug and biologic approvals for children with pediatric rheumatic diseases, particularly juvenile idiopathic arthritis.
Clinical trial conduct in rare pediatric diseases has required global recruitment. Supported or led by the PRCSG, highly responsive, validated, composite measures have been established to assess drug efficacy. For pediatric orphan diseases with high disease burdens, specialized investigative sites and study designs are needed to complete adequately powered trials at the high standard necessary to enable drug labeling by regulatory agencies. Novel trial designs have been utilized for more efficient testing of innovative drug candidates. All these have been developed or co-developed by the PRCSG research network.
Specialized research networks in pediatric rheumatology, such as the PRCSG, have changed the landscape of available therapies and improved overall disease outcomes for children with pediatric rheumatic diseases.
Objective
To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular‐course juvenile idiopathic arthritis (JIA) in the STRIVE registry.
Methods
STRIVE enrolled patients with ...polyarticular‐course JIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA ± MTX). Adverse events (AEs) per 100 patient‐years of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA ± MTX, defined as new users, were evaluated for change in disease activity assessed by the 27‐joint Juvenile Arthritis Disease Activity Score with the C‐reactive protein level (JADAS‐27CRP).
Results
At the 7‐year cutoff date (June 1, 2016), data from 838 patients were available (MTX arm n = 301, ADA ± MTX arm n = 537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA ± MTX arm. Rates of serious infection were 1.5 events/100 patient‐years in the MTX arm and 2.0 events/100 patient‐years in the ADA ± MTX arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA ± MTX arm showed a trend toward lower mean JADAS‐27CRP compared with new users in the MTX arm in the first year of STRIVE.
Conclusion
The STRIVE registry 7‐year interim results support the idea that ADA ± MTX is well tolerated by most children. Registry median ADA exposure was 2.47 (interquartile range 1.0–3.6) years, with 42% of patients continuing ADA at the 7‐year cutoff date.
Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
...This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 29% of 72 patients) than with placebo (37 53% of 70 patients; hazard ratio 0·46, 95% CI 0·27–0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
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•A FHIR-based EHR phenotyping framework is built to classify patient disease status.•An NLP2FHIR pipeline is applied to standardize textual discharge summaries.•A machine learning ...module is implemented using features of FHIR resource instances.•A case study is performed using two obesity datasets.•The FHIR-based approach improves portability of EHR phenotyping.
Standards-based clinical data normalization has become a key component of effective data integration and accurate phenotyping for secondary use of electronic healthcare records (EHR) data. HL7 Fast Healthcare Interoperability Resources (FHIR) is an emerging clinical data standard for exchanging electronic healthcare data and has been used in modeling and integrating both structured and unstructured EHR data for a variety of clinical research applications. The overall objective of this study is to develop and evaluate a FHIR-based EHR phenotyping framework for identification of patients with obesity and its multiple comorbidities from semi-structured discharge summaries leveraging a FHIR-based clinical data normalization pipeline (known as NLP2FHIR).
We implemented a multi-class and multi-label classification system based on the i2b2 Obesity Challenge task to evaluate the FHIR-based EHR phenotyping framework. Two core parts of the framework are: (a) the conversion of discharge summaries into corresponding FHIR resources – Composition, Condition, MedicationStatement, Procedure and FamilyMemberHistory using the NLP2FHIR pipeline, and (b) the implementation of four machine learning algorithms (logistic regression, support vector machine, decision tree, and random forest) to train classifiers to predict disease state of obesity and 15 comorbidities using features extracted from standard FHIR resources and terminology expansions. We used the macro- and micro-averaged precision (P), recall (R), and F1 score (F1) measures to evaluate the classifier performance. We validated the framework using a second obesity dataset extracted from the MIMIC-III database.
Using the NLP2FHIR pipeline, 1237 clinical discharge summaries from the 2008 i2b2 obesity challenge dataset were represented as the instances of the FHIR Composition resource consisting of 5677 records with 16 unique section types. After the NLP processing and FHIR modeling, a set of 244,438 FHIR clinical resource instances were generated. As the results of the four machine learning classifiers, the random forest algorithm performed the best with F1-micro(0.9466)/F1-macro(0.7887) and F1-micro(0.9536)/F1-macro(0.6524) for intuitive classification (reflecting medical professionals’ judgments) and textual classification (reflecting the judgments based on explicitly reported information of diseases), respectively. The MIMIC-III obesity dataset was successfully integrated for prediction with minimal configuration of the NLP2FHIR pipeline and machine learning models.
The study demonstrated that the FHIR-based EHR phenotyping approach could effectively identify the state of obesity and multiple comorbidities using semi-structured discharge summaries. Our FHIR-based phenotyping approach is a first concrete step towards improving the data aspect of phenotyping portability across EHR systems and enhancing interpretability of the machine learning-based phenotyping algorithms.
Abstract
Objective
To determine the efficacy in improving pain and health-related quality of life (HRQOL) of an online self-management program for adolescents with juvenile idiopathic arthritis ...(JIA).
Methods
Youth ages 12–18 years with JIA were recruited from 10 rheumatology clinics across the United States and randomized to complete an online self-management program (n = 144) or an online disease education program (n = 145). Participants in the self-management group worked through multimedia-based modules comprising psychoeducation, training in cognitive–behavioral coping skills and stress management, and other self-management topics over a 12-week period. Participants in the control group viewed a series of preselected quality educational websites about JIA over the same interval. Online content for both groups was made available in English and Spanish to facilitate inclusion of Hispanic participants. Blinded assessment of main outcomes (pain intensity, pain interference, and HRQOL) and process outcomes (disease knowledge, self-efficacy, pain coping, and emotional adjustment) occurred at baseline, posttreatment, and at 6- and 12-month postrandomization follow-up visits.
Results
Participants on average demonstrated significant improvements over the study period in the main outcomes, with no significant group differences in the degree of improvement. Effect sizes for these improvements were small. The amount of improvement in self-efficacy, emotional avoidance coping, disease knowledge, and emotional functioning in part predicted improvement in pain and HRQOL outcomes.
Conclusions
Primarily self-directed online self-management training and online disease education comparably and modestly improve pain and HRQOL in youth with JIA.
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