Tocilizumab as an Effective Treatment Option in Children with Refractory Intermediate and Panuveitis

Purpose: To describe the results of tocilizumab treatment in children with refractory non-anterior uveitis.Methods: A case series of seven children with refractory non-anterior uveitis (onset ≤16 years) with leakage on fluorescein angiogram (FA) were treated with tocilizumab intravenously every 4 weeks (eight mg/kg). Minimum follow-up was 6 months. Reported outcomes are changes in BCVA, central macular thickness (CMT) on OCT image, FA scores, dose of systemic steroids, complications and side effects.Results: In all patients, there was an improvement of macular edema and capillary leakage on FA. The median FA score decreased from 14 (10-18) at baseline to 8 (2-9) after 6 months of treatment (p = .018). The CMT decreased from 321 (314-384) to 295 (255-312) (p = .043). BCVA improved in five eyes and worsened in one eye due to cataract. No systemic or ocular complications were reported.Conclusion: Tocilizumab is an effective therapeutic option for reducing disease activity in children with refractory non-anterior uveitis

Clinical Course and Outcome in Pediatric Idiopathic Chronic Anterior Uveitis

PURPOSE: To examine the clinical course and outcome in children with idiopathic chronic anterior uveitis (iCAU), and to compare the results with those of age-matched children with juvenile idiopathic arthritis−associated uveitis (JIA-U). DESIGN: Retrospective cohort study. METHODS: Data regarding ocular complications, visual acuity, and systemic treatment were retrospectively collected for 2 patient groups that were matched regarding age and year of uveitis diagnosis. Outcome was evaluated using survival analysis. RESULTS: The iCAU and JIA-U groups included 48 patients with 83 affected eyes and 48 patients with 73 affected eyes, respectively. Multivariate analyses showed that iCAU was associated with a higher prevalence of posterior synechiae (adjusted hazard rate [aHR] = 3.63; P <.001) and cataract surgery (aHR = 2.90; P =.006). Baseline visual acuity was worse in the iCAU group compared to the JIA-U group (20/25 vs 20/20, respectively; P <.001), but improved in the iCAU group after 5 years (20/20 vs 20/20, respectively; P =.052). At the 5-year follow-up, the younger children with iCAU (≤8 years of age at diagnosis) had a higher prevalence of posterior synechiae (aHR = 2.56; P =.007), secondary glaucoma (aHR = 16.0; P =.020), and cataract surgery (aHR = 4.79; P =.004) compared to older children with iCAU (≥9 years at diagnosis). CONCLUSIONS: Vision-threatening ocular complications are more common in children with iCAU compared to children with JIA-U, particularly in cases in which the onset of uveitis occurred at ≤8 years of age. However, the long-term vision of these children can be improved with adequate treatment

Next-Generation HLA Sequence Analysis Uncovers Shared Risk Alleles Between Clinically Distinct Forms of Childhood Uveitis

PURPOSE. Classical alleles of the human leukocyte antigen (HLA) complex have been linked to specific entities of pediatric noninfectious uveitis, yet genetic predisposition encoded by the HLA super-locus across the patient population remains understudied. METHODS. We performed next-generation full-length sequencing of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1 in 280 cases. Dense genotype data from 499 Dutch controls from Genome of the Netherlands were imputed using an HLA-specific reference panel (n = 5225 samples from European ancestry). Cases and controls were compared using logistic regression models adjusting for sex. RESULTS. In total, 179 common and rare alleles were detected. Considering all cases and controls, HLA-DQB1*04:02 and HLA-DRB1*08:01 were identified as the principal HLA association, which was mainly driven by 92 cases with juvenile idiopathic arthritis-associated uveitis (JIA-U). The HLA-DQB1*04:02-HLA-DRB1*08:01 haplotype was also the primary association for the phenotypically similar idiopathic chronic anterior uveitis without arthritis (CAU). Also, HLA-DQB1*05:03 was an independent risk allele for CAU, but not in JIA-U. Analysis of 185 cases with other forms of uveitis revealed HLA-wide associations (P < 2.79 × 10 −4) for HLA-DRB1*01:02, HLA-DRB1*04:03, and HLA-DQB1*05:03, which could be primarily attributed to cases with panuveitis. Finally, amino acid substitution modeling revealed that aspartic acid at position 57 that distinguishes the risk allele HLA-DQB1*05:03 (for CAU and panuveitis) from nonrisk alleles, significantly increased the binding capacity of naturally presented ligands to HLA-DQ. CONCLUSIONS. These results uncovered novel shared HLA associations among clinically distinct phenotypes of pediatric uveitis and highlight genetic predisposition affecting the antigen presentation pathway

A Network of Serum Proteins Predict the Need for Systemic Immunomodulatory Therapy at Diagnosis in Noninfectious Uveitis

Purpose: Early identification of patients with noninfectious uveitis requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associated proteomic clusters with the need for IMT during the course of the disease. Design: Multicenter cohort study. Participants: Two hundred thirty treatment-free patients with active noninfectious uveitis. Methods: We used aptamer-based proteomics (n = 1305 proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n = 78) of patients and healthy control participants and independently validated our results in another Dutch cohort (n = 111) and a United States cohort (n = 67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use. Main Outcome Measures: Serum protein levels and use of IMT. Results: Network-based analyses revealed a tightly coexpressed serum cluster (n = 85 proteins) whose concentration was consistently low in healthy control participants (n = 26), but varied among patients with noninfectious uveitis (n = 52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomic location of uveitis (hazard ratio, 3.42; 95% confidence interval, 1.22-9.5; P = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation: r = 0.57, P = 0.006). In an independent Dutch cohort (n = 111), we confirmed that patients with relatively high neutrophil count at diagnosis (> 5.2 × 10 9/L) had a significantly increased chance of requiring IMT during follow-up (hazard ratio, 3.2; 95% confidence interval, 1.5-6.8; P = 0.002). We validated these findings in a third cohort of 67 United States patients. Conclusions: A serum protein signature correlating with neutrophil levels was highly predictive for IMT use in noninfectious uveitis. We developed a routinely available tool that may serve as a novel objective biomarker to aid in clinical decision-making for noninfectious uveitis

Meningococcal ACWY conjugate vaccine immunogenicity in adolescents with primary or secondary immune deficiencies, a prospective observational cohort study

BACKGROUND: Immunization with meningococcal ACWY conjugate vaccine induces protective antibodies against invasive meningococcal disease (IMD) caused by serogroups A, C, W and Y. We studied MenACWY-TT vaccine immunogenicity in adolescents with a heterogenous group of primary and secondary immune deficiency including patients with systemic lupus erythematosus, mixed connective tissue disease, vasculitis, uveitis, 22Q11 syndrome, sickle cell disease, and patients who underwent stem cell transplantation for bone marrow failure. FINDINGS: We enrolled 69 individuals aged 14-18 years diagnosed with a primary or secondary immune deficiency in a prospective observational cohort study. All patients received a single dose of MenACWY-TT vaccine during the catch-up campaign 2018-19 because of the IMD-W outbreak in the Netherlands. Capsular polysaccharide-specific (PS) IgG concentrations against MenACWY were measured before and 3-6, 12, and 24 months after vaccination. Overall, geometric mean concentrations (GMCs) of MenACWY-PS-specific IgG were lower in patients compared to data from healthy, aged-matched controls (n = 75) reaching significance at 12 months postvaccination for serogroup A and W (adjusted GMC ratios 0.26 [95% CI: 0.15-0.47] and 0.22 [95% CI: 0.10-0.49], respectively). No serious adverse events were reported by study participants. CONCLUSIONS: The MenACWY conjugate vaccine was less immunogenic in adolescent patients with primary or secondary immunodeficiency compared to healthy controls, urging the need for further surveillance of these patients and supporting considerations for booster MenACWY conjugate vaccinations in these patient groups

Early oral feeding after pancreatoduodenectomy enhances recovery without increasing morbidity

The aim of this study was to evaluate whether a change in the routine feeding strategy applied after pancreatoduodenectomy (PD) from nasojejunal tube (NJT) feeding to early oral feeding improved clinical outcomes. An observational cohort study was performed in 102 consecutive patients undergoing PD. In period 1 (n = 51, historical controls), the routine postoperative feeding strategy was NJT feeding. This was changed to a protocol of early oral feeding with on-demand NJT feeding in period 2 (n = 51, consecutive prospective cohort). The primary outcome was time to resumption of adequate oral intake. The baseline characteristics of study subjects in both periods were comparable. In period 1, 98% (n = 50) of patients received NJT feeding, whereas in period 2, 53% (n = 27) of patients did so [for delayed gastric empting (DGE) (n = 20) or preoperative malnutrition (n = 7)]. The time to resumption of adequate oral intake significantly decreased from 12 days in period 1 to 9 days in period 2 (P = 0.015), and the length of hospital stay shortened from 18 days in period 1 to 13 days in period 2 (P = 0.015). Overall, there were no differences in the incidences of complications of Clavien-Dindo Grade III or higher, DGE, pancreatic fistula, postoperative haemorrhage and mortality between the two periods. The introduction of an early oral feeding strategy after PD reduced the time to resumption of adequate oral intake and length of hospital stay without negatively impacting postoperative morbidit

Feeding patients with preoperative symptoms of gastric outlet obstruction after pancreatoduodenectomy: Early oral or routine nasojejunal tube feeding?

Early oral feeding is currently considered the optimal routine feeding strategy after pancreatoduodenectomy (PD). Some have suggested that patients with preoperative symptoms of gastric outlet obstruction (GOO) who undergo PD have such a high risk of developing delayed gastric emptying that these patients should rather receive routine postoperative tube feeding. The aim of this study was to determine whether clinical outcomes after PD in these patients differ between postoperative early oral feeding and routine tube feeding. We analyzed a consecutive multicenter cohort of patients with preoperative symptoms of GOO undergoing PD (2010-2013). Patients were categorized into two groups based on the applied postoperative feeding strategy (dependent on their center's routine strategy): early oral feeding or routine nasojejunal tube feeding. Of 497 patients undergoing PD, 83 (17%) suffered from preoperative symptoms of GOO. 49 patients received early oral feeding and 29 patients received routine tube feeding. Time to resumption of adequate oral intake (primary outcome; 14 vs. 12 days, p = 0.61) did not differ between these two feeding strategies. Furthermore, overall complications and length of stay were similar in both groups. Of the patients receiving early oral feeding, 24 (49%) ultimately required postoperative tube feeding. In patients with an uncomplicated postoperative course, early oral feeding was associated with shorter time to adequate oral intake (8 vs. 12 days, p = 0.008) and shorter hospital stay (9 vs. 13 days, p < 0.001). Also in patients with preoperative symptoms of GOO, early oral feeding can be considered the routine feeding strategy after P

Additional file 2 of Meningococcal ACWY conjugate vaccine immunogenicity in adolescents with primary or secondary immune deficiencies, a prospective observational cohort study

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