Objective
To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness ...treatment studies.
Methods
Virtual and face‐to‐face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions.
Results
Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response.
Conclusion
Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.
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 For those patients who maintained clinically inactive disease over the 6 months, anti‐TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare.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.
Objective
To evaluate the efficacy of etanercept in patients with juvenile dermatomyositis (DM) refractory to standard treatment.
Methods
Nine patients with juvenile DM prospectively received ...etanercept 0.4 mg/kg subcutaneous twice weekly concurrently with baseline medications for 12 weeks. Patients were reevaluated 12 weeks (week 24) after stopping etanercept. Outcome measures included a validated Disease Activity Score (DAS), serum muscle enzymes, Childhood Myositis Assessment Scale (CMAS), and nailfold capillaroscopy (NFC).
Results
Six patients completed all visits; 2 patients completed through week 12 and 1 patient stopped after the fifth etanercept dose due to marked worsening of a rash. At week 12, 7 patients had a mild decrease in DAS and 1 patient noted worsening of the DAS. At week 24, 1 patient remained stable, 2 patients had worsening of the DAS, and 3 patients had improvement of the DAS (1 patient with inactive disease), including the patient who worsened while receiving etanercept. This patient and the patient who stopped (worsening rash) both had the tumor necrosis factor α (TNFα) 308A allele. There was a trend of worsening NFC at week 12, while at week 24 improvement of NFC was noted. There was no appreciable change in serum muscle enzymes or CMAS throughout the study.
Conclusion
In this trial of patients with refractory juvenile DM, etanercept did not demonstrate appreciable improvement and some patients noted worsening of disease. Caution should be taken when recommending TNF receptor inhibitors to patients with active symptoms of juvenile DM, and close followup is warranted. Further investigation of the interaction of the TNFα‐308A polymorphism and type I interferon is needed to define the mechanism of TNF blockade in juvenile DM.
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.
Objective
To determine if mycophenolate mofetil (MMF) diminishes skin and muscle disease activity in children with juvenile dermatomyositis (DM), thereby permitting a decrease in corticosteroid dose.
...Methods
A retrospective data review for 50 children with juvenile DM (mean ± SD age 12.2 ± 5.0 years) who had received MMF for 12 months identified the following characteristics: 38 (76%) were girls, 39 (78%) were white, 10 (20%) were Hispanic, and 1 (2%) was African American. The MMF dose and frequency, type of infection, white blood cell (WBC) count, corticosteroid dose, and the validated disease activity score (DAS) subscores for skin (DAS‐S) and muscle (DAS‐M) were obtained.
Results
Twelve months after the start of MMF, the mean ± SD DAS‐S decreased from 5.24 ± 0.29 to 3.72 ± 0.29 (P = 0.001), and the mean ± SD DAS‐M decreased from 2.44 ± 0.39 to 1.17 ± 0.28 (P = 0.002). The mean ± SD prednisone dosage decreased from 0.39 ± 0.06 to 0.23 ± 0.02 mg/kg/day (P = 0.0001), with resumption of linear growth (P = 0.008). The WBC/lymphocyte count was unchanged over the 12 months on MMF. The infection rate was assessed in a subset of 26 children with juvenile DM who were observed for 12 months before the start of MMF and then compared with the ensuing 12 months of MMF therapy. There was no significant difference between the pretreatment period and the first 6 months of MMF therapy (P = 0.44), but the infection rate decreased in months 7–12 (P = 0.001).
Conclusion
MMF appears to be worthy of consideration as an additional therapeutic modality for treatment of children with juvenile DM. These data suggest that the use of MMF decreases skin and muscle disease activity and is steroid sparing. MMF appears to be well tolerated, but patients should be monitored for infection.
Objective
Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for ...Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity.
Methods
We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH‐AI) and the tubulointerstitial activity index (TIAI). High LN‐activity status (versus moderate/low) was defined as NIH‐AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN‐activity status for both NIH‐AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN‐activity status was determined.
Results
The differential excretion of 6 UBMs (neutrophil gelatinase–associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN‐activity (NIH‐AI) status with >92% accuracy and LN‐activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN‐activity status was confirmed by principal component and linear discriminant analyses.
Conclusion
The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.
Objectives
To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN).
Methods
In this prospective study, we evaluated ...kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2 both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy.
Results
Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores Pearson correlation coefficient (
r
) = − 0.49;
p
< 0.0001 but not proteinuria (
r
= 0.20;
p
> 0.05). Similar to the GFR area under the ROC curve (AUC) = 0.72;
p
< 0.01, combinations of osteopontin and adiponectin levels showed moderate accuracy AUC = 0.75;
p
= 0.003 in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP.
Conclusion
In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline.
Key messages
• Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis.
• Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance.
• Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.
Background
Biomarkers in easily obtained specimens that accurately predict uveitis in children with juvenile idiopathic arthritis (JIA) are needed. Aqueous humor has been studied for biomarkers, but ...is not routinely available. We evaluated tears from children with chronic anterior uveitis (CAU) for biomarkers reported in aqueous humor.
In this pilot study, we used Schirmer strips to collect tears from seven children (nine eyes); three children had JIA- associated uveitis (JIA-U) and four had idiopathic disease (I-CAU). Liquid chromatography-tandem mass spectrometry was used to identify and quantify tear proteins. The Mann-Whitney
U
test identified differential tear protein expression between children with JIA-U and those with I-CAU.
Results
S100A9, LAP3, TTR, MIF, sCD14, S100A8, and SAA1 were detected in tears of all children; the same cytokines have been reported in aqueous humor of children with JIA-U. Tears from children with JIA-U had higher expression of proteins associated with inflammatory arthritis (SEMA3G, TIMP1, HEXB, ERN1, and SAA1) than tears from those with I-CAU. In addition, we found higher expression of sCD14, S100A8, and SAA1, but lower expression of S100A9, LAP3, TTR, and MIF, in tears from children with JIA-U compared to tears from those with I-CAU.
Conclusions
Tears contain similar cytokine profiles to aqueous humor in children with CAU and may be a clinically useful source of disease biomarkers. Tears from children with JIA-U also contain cytokines associated with inflammatory arthritis; furthermore, differential expression of other tear proteins as well may provide clues to intrinsic differences between JIA-U and I-CAU, despite their similar clinical phenotypes.
Background The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1-7% in various small studies. As a result of the limited number of research and ...their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers. Methods Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher's exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated. Results 808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA greater than or equal to 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1-1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1-2.9). Conclusions Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD. Keywords: Tissue transglutaminase IgA, tTG IgA, IgA deficiency, Celiac antibodies, Celiac disease, Juvenile Idiopathic Arthritis, Prevalence, Children, Healthy controls
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