Serum phagocyte-derived alarmins S100A8/9 and S100A12 are considered useful for the assessment of inflammatory diseases. Our study evaluated the use of S100 proteins in a pediatric clinical setting ...for estimating disease activity and supporting diagnosis.
Patients (n = 136) who had S100 proteins tested as part of clinical care were included in this study and relevant information obtained from the medical record: C-reactive protein (CRP), disease activity status (inactive: = 0 joint; active: > 0 active joint), systemic symptoms in systemic JIA (sJIA), and symptoms of flare of other autoinflammatory and fever syndromes. Patients were categorized as: sJIA, non-systemic JIA (nsJIA), other defined autoinflammatory syndromes (AID) and systemic undifferentiated recurring fever syndromes (SURFS).
Patients with sJIA (n = 21) had significantly higher levels of S100A8/9 and S100A12 compared to patients with nsJIA (n = 49), other AIDs (n = 8) or SURFS (n = 14) (all p < 0.0001). Compared to CRP area under the receiver operating characteristics curve (AUC) = 0.7, S100 proteins were superior in differentiating sJIA from AID and SURFS AUC = 0.9. S100A8/9 and S100A12 levels were not associated with disease activity in nsJIA, AID or SURFS. S100A8/9 and S100A12 levels were significantly higher in active sJIA compared to inactive (p = 0.0002 and p = 0.0002 respectively).
Compared to other autoinflammatory and fever syndromes, sJIA patients have markedly higher levels of S100A8/9 and S100A12 proteins which may assist with diagnosis. S100 levels slightly outperformed CRP in distinguishing sJIA from other diagnoses and in sJIA disease activity. S100 proteins may aid in monitoring disease activity in sJIA patients.
•Uncontrolled, chronic anterior uveitis leads to ocular morbidity in children.•Failed treatment with methotrexate and adalimumab and/or infliximab is not uncommon.•Alternative biologic agents include ...golimumab, tocilizumab, and abatacept.•Nine patients with resistant disease were successfully treated with alternative biologic agents.
A significant number of children with noninfectious, chronic anterior uveitis (CAU) fail to respond to conventional therapy; however, successful alternative biologic treatments (ABT) have not been well described. This study aims to review the clinical and treatment characteristics of children with CAU who require ABT.
Retrospective, nonrandomized clinical study.
Setting: Tertiary center. Study Population: Children with noninfectious CAU. Observation Procedures: Clinical characteristics, uveitis course, complications, and treatment were compared among patients treated with methotrexate (MTX) monotherapy, conventional TNFα inhibitors (cTNFi), and ABT for >3 months. Main Outcome Measure: Success of ABT (abatacept, tocilizumab, and/or golimumab) in children failing conventional treatment.
Of the 52 children with CAU, 75% had juvenile idiopathic arthritis. CAU was controlled in 15 children receiving MTX monotherapy, 28 receiving cTNFi, and 9 receiving ABT (n = 1, abatacept; n = 3, tocilizumab; n = 5, golimumab). Patients in the ABT group had a greater number of total ocular complications per person before ABT than those in the control groups (3.4 vs 0.7 MTX, P < .001, and 1.5 cTNFi, P < .001, respectively). In all 9 children on ABT, treatment led to control of CAU and topical glucocorticoids tapered to ≤2 drops/d with no new ocular complications.
In this study, alternative biologics (abatacept, golimumab, and tocilizumab) were useful for treating CAU in children who fail MTX and cTNFi therapy. Patients who were controlled on ABT had more disease activity, ocular complications, and anti-cTNFi neutralizing antibodies (before ABT) than those managed with conventional therapy. Larger studies are required to confirm these findings.
Objective
To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti–tumor necrosis factor (anti‐TNF) therapy and the ...occurrence of disease flare following withdrawal of anti‐TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA).
Methods
In this prospective, multicenter study, 137 patients with polyarticular‐course JIA whose disease was clinically inactive while receiving anti‐TNF therapy were enrolled. Patients were observed for an initial 6‐month phase during which anti‐TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti‐TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti‐TNF withdrawal. Spearman's rank correlation test, Mann‐Whitney U test, Kruskal‐Wallis test, receiver operating characteristic (ROC) curve, and Kaplan‐Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti‐TNF withdrawal.
Results
Over the 6‐month initial phase with anti‐TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular‐course JIA; following anti‐TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti‐TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti‐TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti‐TNF withdrawal were inversely correlated with the time to disease flare (r = −0.36).
Conclusion
Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular‐course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.
Purpose:
The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain ...significance (VUS) and novel variants identified in the
GAA
gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of
GAA
variants.
Methods:
We developed an
in vitro
mammalian cell expression and functional analysis system based on guidelines established by the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group for PS3/BS3. We validated the assay with 12 control variants and subsequently analyzed eight VUS or novel variants in
GAA
identified in patients with a positive newborn screen for Pompe disease without phenotypic evidence of infantile-onset disease.
Results:
The control variants were analyzed in our expression system and an activity range was established. The pathogenic controls had GAA activity between 0% and 11% of normal. The benign or likely benign controls had an activity range of 54%–100%. The pseudodeficiency variant had activity of 17%. These ranges were then applied to the variants selected for functional studies. Using the threshold of <11%, we were able to apply PS3_ supporting to classify two variants as likely pathogenic (c.316C > T and c.1103G > A) and provide further evidence to support the classification of likely pathogenic for two variants (c.1721T > C and c.1048G > A). One variant (c.1123C > T) was able to be reclassified based on other supporting evidence. We were unable to reclassify three variants (c.664G > A, c.2450A > G, and c.1378G > A) due to insufficient or conflicting evidence.
Conclusion:
We investigated eight
GAA
variants as proof of concept using our validated and reproducible
in vitro
expression and functional analysis system. While additional work is needed to further refine our system with additional controls and different variant types in order to apply the PS3/BS3 criteria at a higher level, this tool can be utilized for variant classification to meet the growing need for novel
GAA
variant classification in the era of newborn screening for Pompe disease.
ObjectiveTreat-to-target (T2T) strategies are advocated to improve prognosis in childhood-onset SLE (cSLE). Proposed T2T states include SLEDAI score of <4 (SLEDAI-LD), limited corticosteroid use ...(low-CS), and lupus low disease activity state (LLDAS). We sought to compare T2T states for their association with cSLE prognosis under consideration of relevant disease characteristics such as pre-existing damage, race and lupus nephritis (LN).MethodsLongitudinal data from 165 patients enrolled in the Cincinnati Lupus Registry were included. LN presence was based on renal biopsy, and patients were followed up until 18 years of age.ResultsThe 165 patients (LN: 45, white: 95) entered the registry within a median of 0 (IQR: 0–1) year post diagnosis and were followed up for a median of 4 (IQR: 2–5) years during which 80%, 92% and 94% achieved LLDAS, low-CS and SLEDAI-LD. Patients with LN were significantly less likely to achieve any T2T state (all p<0.03) and required a significantly longer time to reach them (all p<0.0001). Over the study period, patients maintained low-CS, SLEDAI-LD or LLDAS for a median of 76% (IQR: 48%–100%), 86% (IQR: 55%–100%) or 39% (IQR: 13%–64%) of their follow-up. Significant predictors of failure to maintain LLDAS included LN (p≤0.0062), pre-existing damage (p≤0.0271) and non-white race (p≤0.0013). There were 22%, 20% and 13% of patients who reached SLEDAI-LD, CS-low and LLDAS and nonetheless acquired new damage. Patients with LN had a higher risk of new damage than patients without LN even if achieving low-CS (p=0.009) or LLDAS (p=0.04).ConclusionsPatients with LN and pre-existing damage are at higher risk of increased future damage acquisition, even if achieving a T2T state such as LLDAS. Among proposed common T2T states, the LLDAS is the hardest to achieve and maintain. The LLDAS may be considered the preferred T2T measure as it conveys the highest protection from acquiring additional disease damage.
In Childhood-Onset Systemic Lupus Erythematosus (cSLE), poor medication adherence rates are very high. Interventions targeting this problem in cSLE are limited thus effective interventions are ...needed. The objective of this study is to examine the feasibility and acceptability an intervention (automated digital reminders + personalized prescribed treatment plan (pPTP)) to improve medication adherence in young adults with cSLE over 3 months.
This is a proof-of-concept randomized controlled study. All participants received SimpleMed+ pillboxes that track adherence. The treatment group received a pPTP, and in month 2, preselected digital reminders for missed doses. Reminders were discontinued after 30 days and adherence data collected. Data analysis was done using t-tests.
Twenty-one participants were approached and nineteen consented to participate, yielding a recruitment rate of 86%. Participants were on average 20.5 years, mostly black (58%) and female (84%). Of the nineteen consented, eleven were randomized to control (57%) and eight to treatment (42%) groups respectively. All participants in the treatment group rated the pillbox as easy to use, notably; none reported boredom with the pillbox or reminders. Also, 88% of participants in the treatment group rated the pillbox as helpful, however, only 50% reported the pPTP taught them new information about lupus or made them more interested in their lupus management.
This is the first use of an electronic pillbox to track adherence to multiple medications in cSLE. The high rating of the pillbox makes it an acceptable method of measuring adherence. Feasibility and acceptability ratings for the intervention were mixed suggesting a there is a subset of cSLE patients for whom this intervention would be beneficial. Future research should focus on a larger trial.
Objective
To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti–tumor necrosis factor (anti‐TNF) therapy in children with polyarticular forms of juvenile ...idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease.
Methods
In 16 centers 137 patients with clinically inactive JIA who were receiving anti‐TNF therapy (42% of whom were also receiving methotrexate MTX) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti‐TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life‐table analysis, t‐tests, chi‐square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare.
Results
Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti‐TNF therapy for the initial 6 months and were included in the phase of the study in which anti‐TNF therapy was stopped. Stopping anti‐TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05).
Conclusion
Over one‐third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti‐TNF therapy. Several predictors of lower likelihood of flare were identified.
Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor ...(TGF)-β1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs.
We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls.
Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels.
IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-β1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects.
IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.
Background/PurposeAchievement of a lupus low disease activity state (LLDAS) has been associated with less organ damage, fewer disease flares, and improved health-related quality of life in children ...with systemic lupus erythematosus (cSLE). No prior studies have evaluated the implementation of lupus disease activity measure collection in the real-world. Our objective was to evaluate the acceptability, appropriateness, and feasibility of implementing a Treat to Target strategy for lupus in the pediatric rheumatology clinic.MethodsThe Pediatric Lupus Understanding Systems (PLUS) collaborative was formed consisting of 5 pediatric rheumatology sites located in children’s hospitals affiliated with academic medical centers in the United States. We operationalized the 5 cLLDAS criteria to collect at the point of care (table 1) with plans for implementation phase 1 to track collection of each criteria at cSLE visits on a monthly basis. We completed a baseline implementation assessment using the Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure. Each measure consists of 4 domains assessed on a Likert scale of 1–5 (1=completely disagree to 5=completely agree). Mean response was calculated for each domain. Barriers to cLLDAS criteria collection were also identified.ResultsWe collected a baseline implementation assessment from each PLUS collaborative site leader (n=5). Sites reported a range of number of pediatric rheumatology providers (5–18), most had trainees in clinic, and 60% have mid-level providers (table 2). The approximate number of patients with cSLE seen in 2022 varied from 73–150 with a broad mix of insurance. All major electronic health record (EHR) vendors are represented. Implementing collection of cSLE disease activity measures and a Treat to Target strategy in the pediatric rheumatology clinic was largely found to be acceptable and appropriate (table 3). Scores for feasibility of the intervention were less positive. Themes of identified barriers to collection of cLLDAS criteria included: need for EHR adjustments to collect discrete data, availability of laboratory results to calculate disease activity during clinic visit, preexisting systems to collect physician global assessment on 0–10 scale, and physician burnout to change.ConclusionImplementation of a treat to target approach to care of patients with cSLE is acceptable and appropriate although will require a dedicated effort to be feasible. A key determinant to monitoring real-world performance is ability to customize EHR with discrete data fields. Next steps are to use implementation facilitation via monthly meetings to improve performance from baseline.Abstract 1305 Table 1Criteria required to calculate cLLDAS operationalized for collection at the point of care. Implementation Phase 1 SLEDAI-2K completion New disease activity attestation Physician global assessment (0–3) completion Prednisone (or equivalent) dose documented Standard medication dose attestation Abstract 1305 Table 2Baseline characteristics of the pediatric rheumatology sites participating in PLUS collaborative. Site Providers Trainees Mid Level Providers Patients with cSLE seen in 2022 EHR Vendor 1 18 Yes Yes 110 Epic 2 11 Yes No 150 Epic 3 8 No No 91 Cerner 4 5 Yes Yes 73 Allscripts 5 7 Yes Yes 75 Cerner Abstract 1305 Table 3Mean response across PLUS collaborative sites to each implementation measure domain using 5-point Likert scale. Acceptability of Intervention 1) Intervention meets my approval. 4.8 2) Intervention is appealing to me. 4.8 3) I like the intervention. 4.6 4) I welcome the intervention. 4.6 Intervention Appropriateness 1) The intervention seems fitting. 4.6 2) The intervention seems suitable. 4.2 3) The intervention seems applicable. 4.6 4) The intervention seems like a good match. 4.4 Feasibility of Intervention 1) The intervention seems implementable. 4.0 2) The intervention seems possible. 4.0 3) The intervention seems doable. 4.0 4) The intervention seems easy to use. 3.0
BackgroundPhysician Global Assessment of Disease Activity (PhGA) are commonly used outcome measures in pediatric rheumatology. For childhood-onset systemic lupus erythematosus (cSLE), the traditional ...visual analog scale (range: 0 – 10; 0=inactive; 10=very active; PhGA0–10) but also the SELENA-SLEDAI (range: 0–3; 0= none, 1=mild, 2=moderate, 3=severe; PhGA0–3) are used to measure treatment response, flare, and Lupus Low Disease Activity Status (LLDAS) with PhGA0–3 ≤1. Thus, the purpose of this study was to compare the measurement properties of the PhGA0–10 and the PhGA0–3 in cSLE and with scores of the SLEDAI-2k, and the SELENA-SLEDAI.MethodsSecondary data analysis from a convenience sample of 100 cSLE followed every 3 months for up to 7 visits.1 Ratings of PhGA0–10, PhGA0–3, parent assessment of patient well- being (ParGA; range: 0= very poorly, 10=very well), SLEDAI-2k and SELENA-SLEDAI were compared. After linear transformation of PhGA0–10 to a 0–3 range (tPhGA0–10) frequency of PhGA0–3≤1 were compared.ResultsIn 601 visits, mean (SD)/median (range) of PhGA0–10, PhGA0–3, SLEDAI-2K and SELENA-SLEDAI were 2.13 (1.87)/2 (0–10), 0.79 (0.64)/1(0–3), 4.63 (4.14)/4 (0–28) and 4.51 (4.1)/4 (0–32) respectively. PhGA0–10 were moderately correlated with PhGA0–3 (r=0.73; p<0.0001; figure 1) with more variability for PhGA0–3 ≥2. ParGA was weakly correlated with PhGA0–10, PhGA0–3, SLEDAI-2k and SELENA-SLEDAI scores (r = -0.34, -0.30, -0.19 and -0.20). SELENA-SLEDAI and SLEDAI-2k scores were highly (r=0.98) correlated with each other. However, SLEDAI-2K/SELENA-SLEDAI scores were weakly correlated with PhGA0–3 (r=0.28/0.28; p <.001) and moderately correlated with PhGA0–10 (r= 0.56/0.54; p <.0001). There were 490/497 of 601 visits with PhGA0–3 ≤1/tPhGA0–10 ≤1 Kappa (SE) =0.59 (0.04), McNemar p=0.4.ConclusionUsing the traditional PhGA0–10 in cSLE yields almost identical LLDAS rates compared to the PhGA0–3. Given its closer association with the scores of disease activity indices in cSLE, use of the PhGA0–10 may be preferable in pediatric populations.ReferenceMina R, Klein-Gitelman MS, Nelson S, Eberhard BA, Higgins G, Singer NG, Onel K, Tucker L, O’Neil KM, Punaro M, Levy DM, Haines K, Martini A, Ruperto N, Lovell D, Brunner HI. Validation of the systemic lupus erythematosus responder index for use in juvenile- onset systemic lupus erythematosus. Ann Rheum Dis. 2014 Feb;73(2):401–6. PMID: 23345596.Abstract 1303 Figure 1Relationship of physician global assessment of disease activity traditional visual analog scale (PhGA0–10) with the SELENA-SLEDAI scale (PhGA0–3)
PDF
