Search

Objective: To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. Methods: Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin‐1 (IL‐1)–mediated diseases including neonatal‐onset multisystem inflammatory disease (NOMID) and deficiency of the IL‐1 receptor antagonist (DIRA). Results: A 4‐year‐old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute‐phase reactants. She had a 17.8‐kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long‐lasting remission receiving IL‐1 blockade with canakinumab. Compared to controls, monocytes and monocyte‐derived M1‐like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL‐1β secretion. In contrast, lipopolysaccharide‐stimulated, monocyte‐derived, M2‐like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL‐8, IL‐6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL‐1 (but not IL‐6) blockade. Conclusion: We report 2 novel compound heterozygous disease‐causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2‐like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL‐1–mediated autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To determine the long-term safety and efficacy of rilonacept, an anti-interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA). Methods In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4-week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open-label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated. Results Twenty-four patients entered the double-blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment-related adverse events were observed. Conclusion Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in >50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated. [ABSTRACT FROM AUTHOR]

Background/Purpose: The nuclear oncoprotein DEK is a biochemically distinct protein, modulating heterochromatin integrity, chemoattractant of neutrophils and T-cells and vital for the formation of neutrophil extracellular traps (NETs). NETs are important for resolution of inflammation suggesting that DEK contributes to the development of autoimmune diseases. High levels of DEK autoantibodies have been found in several autoimmune diseases including juvenile idiopathic arthritis (JIA) but their role in disease pathogenesis is not clear. Since DEK and DEK autoantibodies can contribute to the development of immune complexes and NET formation we suggest that DEK antibody levels can predict flare with the discontinuation of anti-TNF therapy. Methods: In16 pediatric rheumatology centers, sera samples were collected from 137 children with polyarticular JIA with clinically inactive disease (CID) on anti-TNF therapy. The therapy was stopped and disease activity was monitored for at least 8 months or until disease flare. DEK antibody levels were measured in sera collected at time of enrollment and 6 months (when anti-TNF therapy was stopped) by ELISA. DEK antibody levels relative to healthy controls were calculated by area under the curve (AUC), expressed as unit-free ratios. Results: 103 females and 34 males patients were enrolled. Mean age 11.3 years and disease duration 5.0 years. JIA included: 13% extended oligoarthritis, 74% polyarthritis rheumatoid factor (RF) negative and 12 % polyarthritis RF positive and 46% positive ANA. 77% were taking etanercept, 18% adalimumab, 5% infliximab and 40% methotrexate. 31 patients (23%) discontinued the study prior stopping the therapy for various reasons, including loss of CID. Of 106 subjects who stopped the therapy, 39 (37%) flared within 8 months (mean of 104.8 days). 67 subjects (63%) had no flares within 8 months after stopping the therapy. 71 out of 106 patients samples were analyzed thus far for DEK antibody levels. DEK antibody level ratios compared to healthy controls was −0.36 (some patients had lower antibody levels than did healthy controls) to 1.41, median ratio of 0.11 (Q1-Q3 of 0.09-0.24) and 0.13 (SD, 0.3). High levels of DEK antibodies, mean and SD of 0.209 ± 0.36 were detected in the 21 patients that flared within 8 months compared to lower levels of DEK antibodies (0.09 ± 0.27) in 50 patients with CID for at least 8 months (ANOVA P= 0.1832). Negative correlation was observed between the days to flare and DEK antibody levels (spearman rho = −0.31, P = 0.07), suggesting that when therapy stopped, patients with higher levels of DEK antibodies will flare sooner with estimated odds ratio of 3.3 (95% CI, 0.61, 18.0), suggesting that each unit increase in DEK antibodies is associated (P = 0.17) with more than a 2-fold increased risk of flare within 8 months. Conclusion: In children with JIA extended oligoarthritis and polyarthritis on anti-TNF therapy that maintain CID for at least 6 months while on therapy, high DEK antibody levels may be correlated with flare within the first 8 months after stopping the therapy. This study suggests that DEK antibody levels can predict the outcome of discontinuation of anti-TNF therapy, although more patient samples need to be analyzed from this study and future studies. [ABSTRACT FROM AUTHOR]

Background/Purpose: Anti-TNF therapy for polyarticular forms (extended oligo-, rheumatoid factor +/− polyarthritis) of JIA (PF-JIA) results in up to 50% of patients (pts) demonstrating clinically inactive disease (CID). This study determined the pattern of serum S100A12 levels at the time of withdrawal of anti-TNF therapy. Methods: In 16 centers, 137 pts with PF-JIA in CID on anti-TNF therapy were enrolled and followed for at least 14 months (mos). During the first 6 study mos pts were maintained on anti-TNF therapy and if CID was maintained, then anti-TNF therapy was stopped. Background medications were stable. S100A12 levels were obtained at the time of anti-TNF withdrawal. The primary outcome was disease 'flare' defined by worsening of ≥30% in ≥ 3 of the 6 core set variables, with no more than 1 improving by ≥30%. Parameters had to increase by at least the following amounts: MD and parent globals by 2 units, active and limited joints by 2, CHAQ by 0.125 and ESR from normal to abnormal. Results: 24 pts failed to maintain CID in the first 6 study mos and 7 pts were discontinued from the study for other reasons. 106 pts were available for this analysis of whom 39 (37%) experienced flare. The S100A12 levels at time of anti-TNF withdrawal did not differ significantly in regards to JIA type, presence of ANA, MTX co-therapy, or type of anti-TNF therapy and did not correlate with previous duration of CID. Globally, S100A12 at the time of withdrawal did not differ significantly according to disease flare (flare 73 +/− 117 ng/ml, no flare 80 +/− 220 ng/ml) (median ++/− standard deviation). Receiver-operating curve (ROC) analysis computing S100A12 at time of anti-TNF withdrawal against flare for the entire study period demonstrated an area-under-the-curve (AUC) of 0.51, 95% confidence interval (CI) 0.39-0.62, for prediction of flare within 60 days AUC 0.66, 95% CI 0.56-0.75, for prediction of flare within 90 days AUC 0.64, 95% CI 0.54-0.74 and for prediction of flare within 120 days AUC 0.54, 95% CI 0.44-0.64. The S100A12 level at time of withdrawal correlated inversely with the time to flare (Spearman rank correlation = −0.34, p = 0.05). Flares occurred earlier in pts with predefined high (>120 ng/ml) vs. low (≤120 ng/ml). S100A12 levels at time of withdrawal among pts who flared (median time to flare 36 vs. 114 days, p = 0.02). The overall flare rate in patients with high vs. low S100A12 levels at time of withdrawal was 35% vs. 38%, respectively. Kaplan-Meier analysis of disease flare in pts with high vs. low S100A12 levels at time of withdrawal also demonstrated a trend towards earlier disease flare in pts with high S100A12 levels (log rank test significance 0.07). Conclusion: In this prospective study, a substantial proportion of pts with PF-JIA experienced disease flare after anti-TNF withdrawal. Serum S100A12 levels at time of anti-TNF withdrawal did not differ between pts subsequently experiencing disease flare and those not experiencing flare throughout the entire study period. However, pts with high S100A12 levels (>120 ng/ml) experienced earlier disease flare. [ABSTRACT FROM AUTHOR]

Background/Purpose: Treatment with anti-TNF therapies for polyarticular forms (extended oligoarthritis, rheumatoid factor [RF] +/− polyarthritis) of JIA (PF-JIA) results in up to 50% of patients (pts) demonstrating clinically inactive disease (CID). Serum S100A12 protein levels have been demonstrated to predict failure to maintain CID after withdrawal of methotrexate (MTX). This study determined the pattern of baseline serum S100A12 levels during CID on anti-TNF therapy. Methods: In 16 centers, 137 pts with PF-JIA in CID on anti-TNF therapy were enrolled. During the first 6 study months patients were maintained on anti-TNF therapy and monitored. If CID was maintained for first 6 study months, then anti-TNF therapy was stopped. Pts were followed for up to 14 mos total or until loss of CID on anti-TNF therapy or until flare off anti-TNF therapy, whichever came first. Background medications were stable throughout the study. Blood for serum S100A12 measurement was drawn at study enrollment. S100A12 measurements were obtained via a validated ELISA. The secondary outcome of this part of the analysis was failure to maintain CID during the first 6 study months. Results: 7 pts were discontinued from the study for reasons other than inability to maintain CID and 130 patients were available for analysis. 24 pts failed to maintain CID during the first 6 study months. Demographic and clinical details are reported elsewhere during this conference. Baseline S100A12 levels did not differ significantly according to sex (female 96 +/− 229 ng/ml, male 66 +/− 144 ng/ml), JIA subtype (extended oligo 91 +/− 199 ng/ml, poly RF- 93 +/− 219 ng/ml, poly RF+ 114 +/− 157 ng/ml) presence of ANA (positive 83 +/− 174 ng/ml, negative 96 +/− 240 ng/ml), MTX co-therapy (yes 84 +/− 259 ng/ml, no 95 +/− 167 ng/ml) or type of anti-TNF therapy (adalimumab 114 +/− 140 ng/ml, etanercept 90 +/− 214 ng/ml, infliximab 120 +/− 330 ng/ml) (values given as median +/− standard deviation) and did not correlate with duration of previous duration of inactive disease (r = −0,06). Globally, S100A12 did not differ significantly according to failure to maintain CID (failure to maintain CID 100 +/− 188 ng/ml, maintaining CID 93 +/− 216 ng/ml). Based on a predefined normal level of S100A12 of <120 ng/ml, 87 (66%) of patients demonstrated normal S100A12 levels and 43 (33%) of patients demonstrated elevated S100A12 levels. However, receiveroperating curve analysis computing baseline S100A12 against failure to maintain CID demonstrated an areaunder-the-curve of 0,47 (95% confidence interval 0.33-0.62). Conclusion: In this prospective multicenter study, baseline S100A12 levels in pts with PF-JIA were elevated in a substantial proportion of pts but did not differ among groups according to multiple parameters. Serum S100A12 did not predict failure to maintain CID. [ABSTRACT FROM AUTHOR]

Background/Purpose: Treatment with anti-TNF therapies (anti-TNF) for polyarticular forms (extended oligo, Poly RF +/−) of JIA (PF-JIA) results in >50% demonstrating clinically inactive disease (CID). The aims of this study were to determine the frequency, timing and predictors of flare upon withdrawal of anti-TNF in PF-JIA in CID. Methods: In 16 centers 137 children with PF-JIA in CID on anti-TNF were enrolled and followed for ≥14 mos. If CID was maintained for the first 6 study mos, then anti-TNF was stopped. The primary outcome variable was a validated definition of disease flare within 8 months after stopping anti-TNF. Background meds were stable. Blood for S100, DEK, DNA and RNA was drawn for current and future biomarker and genetic studies. Results: The study population included 18 (13%) extended oligarticular, 17 (12%) RF+ Poly and 102 (74%) RF- Poly JIA patients. At enrollment, age (mean/median/range) was 11.3/11.6/3.4-20.1 yrs; disease duration was 5.0/4.1/0.6-18.6 years; 103 (75%) were females and 64 (47%) were ANA+. Duration of CID at baseline was 1.2/0.5/1 day-12.1 yrs. Anti-TNF was etanercept in 106 (77%), 25 (18%) adalimumab and 6 (5%) infliximab. 40% were on MTX at baseline (mean/median dose 0.4/0.4 mg/kg/week). Other meds: 1 leflunomide, 2 hydroxychloroquine, and 1 prednisolone. 31 (23%) subjects were discontinued from the study in the first 6 mos: 23 (17%) due to loss of CID, 5 (4%) med noncompliance, 2 (1%) moved/LTF, 1 (1%) ILAR subtype changed (oligo to psoriatic). For the extended oligo, Poly RF− and Poly RF+ categories 94%, 82% and 60%, respectively, maintained CID for the first 6 months (c2 6.7, p 0.03). ANA status, MTX use, and type of anti-TNF were not associated with the ability to maintain CID (c2 p values 0.48, 0.14, and 0.75, respectively). 106 (77%) subjects maintained CID for the first 6 months and stopped anti-TNF as per protocol. 67/106 (63%) maintained CID for ≥8 mos off anti-TNF while 39 (37%) flared. Time without flaring after stopping anti-TNF therapy was duration from the month 6 visit to the last study visit (mean/median/range for duration of followup was 249/250/126-322 days). The mean/median/range for time to flare was 108/105/7-271 days. Time to flare (days) for etanercept was 105/105/7-271, adalimumab 119/120/28-238 and infliximab 28/28/28. Flare was seen in 47% (8/17) extended oligo, 37% (30/80) poly RF- and 11% (1/9) poly RF+ ((c2 p-value 0.19). In those on background MTX, 33% (13/40) flared at a mean of 90 days, while those not on background MTX, 39% (26/66) flared at a mean of 113 days ((c2 p-value 0.48). Using univariate analysis of variance, only weak correlations of MTX dose, disease duration, and CID duration with flare/no flare were seen (Spearman correlations −0.03, −0.17, −0.19, respectively). Conclusion: In this prospective multicenter study, 77% of the PF-JIA patients were able to maintain CID for the first 6 months on anti-TNF. Discontinuation of anti-TNF in PR-JIA (who have demonstrated on average 1.8 years of CID) resulted in a flare rate of 37% within 8 mos. Clinical parameters had only minimal predictive ability. Ongoing work includes biomarker identification and continued follow-up of the cohort. [ABSTRACT FROM AUTHOR]