The patients, aged between 5 and 12 years, exhibited the phenotypic variability associated with TMEM173-activating mutations,2-4 with lung disease and systemic inflammation being the major features ...in patient 1 (P1) and patient 3 (P3), while in patient 2 (P2) skin involvement was most prominent (Fig 1; see Supplemental Text and Table E1 in this article's Online Repository at www.jacionline.org). Modest and incomplete downregulation of ISG was recently described in splenic B cells of mice treated with tofacitinib, a JAK1/3 inhibitor, with differential signaling effects suggesting currently poorly understood facets of IFN regulation.9 In this regard, our kinetic ex vivo experiments provide insights into the rapid dynamic changes in IFN signaling secondary to JAK1 blockade.
An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ–positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, ...comprising at least two 5-day courses of Ara-C (1 g/m2 per day) plus cladribine (9 mg/m2 per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.
•Patients with LCH, risk organs, refractory to standard VBL-steroid regimen have a poor survival, ∼30%.•In a phase 2 study, with 5 years' median follow-up, cladribine and Ara-C was shown to improve the survival up to 85% for this group.
Henoch-Schönlein purpura (HSP) is the most common immunoglobulin A-mediated systemic vasculitis in childhood. We studied immune dysregulation in HSP by analyzing regulatory T (Treg), T helper 3 ...(Th3), and regulatory B cell (Breg) subpopulations that might intervene in immune activation, IgA production, and HSP clinical manifestations.
This prospective study included 3 groups of children: 30 HSP on acute phase, 30 HSP on remission, and 40 healthy controls (HCs) matched on age. Treg, Breg, and Th3 were analyzed by flow cytometry. Serum immunoglobulin and cytokine levels were quantified by ELISA and Luminex.
Treg frequencies were higher in acute HSP than in remitting HSP and HCs (6.53% 4.24; 9.21 vs. 4.33% 3.6; 5.66, p = 0.002, and vs. 4.45% 3.01; 6.6, p = 0.003, respectively). Activated Th3 cells (FoxP3 + Th3 cells) tend to be more abundant in HSP than in HCs (78.43% 50.62; 80.84 vs. 43.30% 40.20; 49.32, p = 0.135). Serum IgA, IL-17, and latency-associated peptide (a marker of the anti-inflammatory cytokine TGF-beta production) were significantly and inflammatory cytokines TNF-alpha, IL-1-beta, and IL-6 were non-significantly higher in HSP than HCs. Bregs were identical between the groups, but, in patients with renal impairment, Breg percentage was lower compared to those without. Treg removal in PBMC culture resulted in an increase in IgA production in HSP proving a negative regulatory role of Tregs on IgA production.
In pediatric HSP, immune activation persists in spite of an increase in Th3 and Tregs. Th3 could be involved in IgA hyperproduction, inefficiently downregulated by Tregs. Lack of Bregs appears linked to renal impairment.
The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non‐Langerhans cell histiocytosis (‐LCH) subtypes. A cohort of ...415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E. Most BRAFWT samples were analyzed by next‐generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim‐Chester disease, 21 Rosai‐Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non‐BRAFV600E‐mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non‐MAP‐kinase pathway genes (n = 5). Wild‐type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ‐risk involvement and neurodegeneration. MAP‐kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild‐type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP‐kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.
Castleman disease (CD) is a rare non-malignant lymphoproliferation of undetermined origin. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis ...confirmation is based on histopathological findings in a lymph node. We attempted to survey all cases of paediatric CD identified to date in France to set up a national registry aiming to improve CD early recognition, treatment and follow-up, within the context of a new national reference center (http://www.castleman.fr).
In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the paediatric rheumatology society and the Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory.
We identified 23 patients (12 girls) with a diagnosis of UCD (n = 17) and MCD (n = 6) between 1994 and 2018. The mean age at first symptoms was 11.47 ± 4.23 years for UCD and 8.3 ± 3.4 years for MCD. The mean diagnosis delay was 8.16 ± 10.32 months for UCD and 5.16 ± 5.81 years for MCD. In UCD, the initial symptoms were isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7); fever was present in 3 patients. Five patients with MCD presented fever. No patients had HIV or human herpesvirus 8 infection. Autoinflammatory gene mutations were investigated in five patients. One patient with MCD carried a K695R heterozygous mutation in MEFV, another patient with MCD and Duchenne myopathy carried two variants in TNFRSF1A and one patient with UCD and fever episodes carried two heterozygous mutations, in IL10RA and IL36RN, respectively. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatment of MCD included tocilizumab, rituximab, anakinra, steroids, chemotherapy, and splenectomy. Overall survival after a mean of 6.1 ± 6.4 years of follow-up, was 100% for both forms.
Paediatric CD still seems underdiagnosed, with a significant diagnosis delay, especially for MCD, but new international criteria will help in the future. Unlike adult CD, which is strongly associated with HIV and human herpesvirus 8 infection, paediatric CD could be favored by primary activation of innate immunity and may affect life expectancy less.
Summary
The nucleoside analogue, 2‐chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO−) involvement. However, ...we lack data on long‐term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long‐term tolerance. This study included 44 children from the French LCH registry, treated for a RO− LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3–19·7 years) and the median follow‐up after was 5·4 years (range, 0·6–15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five‐year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases 72% below absolute lymphocyte count (ALC) of 0·5 G/l, was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five‐year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long‐term therapy for treating patients with RO− LCH. Appropriate management of induced immune deficiency is mandatory.
Despite their distinct etiology, several lines of evidence suggest that innate immunity plays a pivotal role in both juvenile idiopathic arthritis (JIA) and septic arthritis (SA) pathophysiology. ...Indeed, monocytes and dendritic cells (DC) are involved in the first line of defense against pathogens and play a critical role in initiating and orchestrating the immune response. The aim of this study was to compare the number and phenotype of monocytes and DCs in peripheral blood (PB) and synovial fluid (SF) from patients with JIA and SA to identify specific cell subsets and activation markers associated with pathophysiological mechanisms and that could be used as biomarkers to discriminate both diseases. The proportion of intermediate and non-classical monocytes in the SF and PB, respectively, were significantly higher in JIA than in SA patients. In contrast the proportion of classical monocytes and their absolute numbers were higher in the SF from SA compared with JIA patients. Higher expression of CD64 on non-classical monocyte was observed in PB from SA compared with JIA patients. In SF, higher expression of CD64 on classical and intermediate monocyte as well as higher CD163 expression on intermediate monocytes was observed in SA compared with JIA patients. Moreover, whereas the number of conventional (cDC), plasmacytoid (pDC) and inflammatory (infDC) DCs was comparable between groups in PB, the number of CD141
cDCs and CD123
pDCs in the SF was significantly higher in JIA than in SA patients. CD14
infDCs represented the major DC subset in the SF of both groups with potent activation assessed by high expression of HLA-DR and CD86 and significant up-regulation of HLA-DR expression in SA compared with JIA patients. Finally, higher activation of SF DC subsets was monitored in SA compared with JIA with significant up-regulation of CD86 and PDL2 expression on several DC subsets. Our results show the differential accumulation and activation of innate immune cells between septic and inflammatory arthritis. They strongly indicate that the relative high numbers of CD141
cDC and CD123
pDCs in SF are specific for JIA while the over-activation of DC and monocyte subsets is specific for SA.
Background Most children with primary immunodeficiencies (PIDs) now reach adulthood. However, few studies have evaluated their health status and health-related quality of life (HRQoL). Objective To ...investigate long-term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the French Childhood Immune Deficiency Long-term Cohort. The data collected were used to assess the physical health condition of patients who reached adulthood and the effect on their quality of life. Methods Patients were asked to complete health status questionnaires. A severity score (grade 1 mild to grade 4 life-threatening) was assigned to each health condition. The HRQoL of patients was compared with age- and sex-matched French normal values by using the 36-item Short-Form Survey (SF-36) HRQoL questionnaire. Results Among 329 participants, the mean age at evaluation was 27.6 years, with a 21-year mean follow-up after diagnosis; 43% reported at least 1 grade 4 health condition, and 86% reported at least 1 grade 3 (severe) or 4 health condition. Twenty-five (7.6%) patients had been treated for cancer. Compared with the French normal values, adults with PIDs scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3-4 health conditions was highly significant for all physical and mental domains. Conclusion Adults with PIDs diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population.
PDF
