Abstract
Objectives
Excessive and inappropriate production of pro-inflammatory cytokines plays a key role in Still’s disease. Janus kinase inhibitor (JAKi) agents mainly block pro-inflammatory ...cytokine pathways, notably IL-6 and IFN. The objective was to assess the efficacy and safety of JAKi agents in difficult-to-treat systemic JIA or adult-onset Still’s disease (AOSD).
Methods
This retrospective study was based on a national survey conducted in the departments of rheumatology, paediatric rheumatology and internal medicine of French hospitals regarding systemic JIA and AOSD patients who received JAKi agents. The data were collected with a standardized questionnaire and analysed at different times (treatment initiation, months 1, 3 and 6 and the end of follow-up).
Results
Nine patients (seven adults) were included. All patients showed inadequate response to CS or conventional synthetic or biologic DMARDs. Baricitinib was used in five patients, ruxolitinib in two, tofacitinib in two and upadacitinib in one. A JAKi was used combined with CS in all but two patients. A JAKi was associated with anakinra and CS in one patient, and with MTX, anakinra and CS in another. The median (range) follow-up was 16 (1–33) months. Two cases out of nine showed complete remission, 3/9 partial response and 4/9 treatment failure. At the last visit, CS could be decreased but not stopped. Tolerance of the JAKi was acceptable (no severe adverse events).
Conclusion
JAKi agents may be a therapeutic option for some patients with difficult-to-treat Still’s disease, especially those with partial response to medium- or high-dose CS or biologics.
•Paediatric TAK are more severe with more inflammation and kidney damages.•Prognosis is worse with more relapses and death.•Rapid initiation of biotherapy might be a key to avoid those complications.
...We aimed to compare clinical spectrum and outcome between adults and children with Takayasu's arteritis (TAK) in a European population.
We made a nationwide retrospective observational study between 1988 and 2019. All adult patients met the ACR diagnostic criteria for TAK and all children met the EULAR/PRINTO/PRES criteria for paediatric TAK.
We identified 46 children and 389 adults with TAK. The male to female ratio was 34/46 (0.74) in the paediatric group compared to 241/274 (0.88) in the adult group (P<0.05). Children presented with significantly more systemic symptoms; i.e., fever (P<0.05), fatigue (P<0.001), weight loss (P<0.001), abdominal pain (P<0.05), and myalgia (P<0.05) while adults had more upper limb claudication (P<0.01). Topography of the lesions differed significantly between the two groups: adults had more damage at the cerebral vasculature (P<0.01), upper and lower limbs (P<0.001) while children had more kidney lesions (P<0.05). Children TAK had more frequent (P<0.01) and higher (P<0.001) biological inflammation than adults. Children received higher dose-weight of corticosteroids (P=0.001) and less biotherapy (P<0.010) at diagnosis. Relapses (P<0.05) and death (8.6% vs 4.9%) were more frequent in children TAK than in adults.
Paediatric TAK seems more severe than adult TAK. Therefore, paediatrics patients may require closer monitoring and systemic use of biological treatment.
Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase DNA-PK) crucial for DNA double-strand break ...repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH 2 and TH 1 but not TH 17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro . The latter defect correlated in vivo with production of anti–calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.
•Therapeutic alliance is high between JIA children and paediatric rheumatologists.•The level of therapeutic alliance is associated with that of therapeutic observance.•Disease activity influences ...negatively therapeutic alliance.
Therapeutic alliance (TA) is the agreement between caregiver and patient during the care process. Therapeutic adherence is a major issue for the management of Juvenile Idiopathic Arthritis (JIA) requiring child's strong ability to follow treatments. The aim of this study was to evaluate the relationship between TA and adherence in patients with JIA.
Observational, cross-sectional, multicenter study. Children, with JIA, aged 8-16, were included. Children, parents and physicians completed the Helping Alliance Questionnaire (HAQ-CP) for assessing TA. Adherence was measured using the Child/Parent Adherence Report Questionnaire (CARQ & PARQ). Demographic data, disease characteristics, current treatments and social environment were collected. The univariate relationship between TA and adherence, was studied by Pearson correlation coefficient. The multivariate analysis used a multiple linear regression model.
A total of 119 patients were included: 68.9% girls, mean age (SD) 12.4 (2.9) years, disease duration 73.1 (48.2) months. JIA was in remission (52%), in low activity (32%) and active (16%). TA scores were high (≥80/100) for children, parents and physicians. HAQCP was highly correlated with CARQ (r=0.31; P<0.001) PARQ (r=0.37; P<0.001). In univariate analysis, disease activity (P<0.05), place of residence (P<0.01) and family status (P<0.01) were associated with child's TA. In multivariate analysis, only the place of residence (P<0.001) and the family status (P<0.05) remained associated with TA.
TA strongly influences therapeutic adherence and therefore may be important for treatment effectiveness.
Background
In multisystem inflammatory syndrome in children (MIS-C), diagnostic delay could be associated with severity. This study aims to measure the time to diagnosis in MIS-C, assess its impact ...on the occurrence of cardiogenic shock, and specify its determinants.
Methods
A single-center prospective cohort observational study was conducted between May 2020 and July 2022 at a tertiary care hospital. Children meeting the World Health Organization MIS-C criteria were included. A long time to diagnosis was defined as six days or more. Data on time to diagnosis were collected by two independent physicians. The primary outcome was the occurrence of cardiogenic shock. Logistic regression and receiver operating characteristic curve analysis were used for outcomes, and a Cox proportional hazards model was used for determinants.
Results
Totally 60 children were assessed for inclusion, and 31 were finally analyzed 52% males, median age 8.8 (5.7–10.7) years. The median time to diagnosis was 5.3 (4.2–6.2) days. In univariable analysis, age above the median, time to diagnosis, high C-reactive protein, and high N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with cardiogenic shock odds ratio (OR) 6.13 (1.02–36.9), 2.79 (1.15–6.74), 2.08 (1.05–4.12), and 1.70 (1.04–2.78), respectively. In multivariable analysis, time to diagnosis ≥ 6 days was associated with cardiogenic shock adjusted OR (aOR) 21.2 (1.98–227). Time to diagnosis ≥ 6 days had a sensitivity of 89% and a specificity of 77% in predicting cardiogenic shock; the addition of age > 8 years and NT-proBNP at diagnosis ≥ 11,254 ng/L increased the specificity to 91%. Independent determinants of short time to diagnosis were age < 8.8 years aHR 0.34 (0.13–0.88), short distance to tertiary care hospital aHR 0.27 (0.08–0.92), and the late period of the COVID-19 pandemic aHR 2.48 (1.05–5.85).
Conclusions
Time to diagnosis ≥ 6 days was independently associated with cardiogenic shock in MIS-C. Early diagnosis and treatment are crucial to avoid the use of inotropes and limit morbidity, especially in older children.
Abstract Objective Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and ...laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE. Methods GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE (clinicaltrials.gov # NCT01992666 ). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE ( n = 10) and familial SLE ( n = 12) – both presumed to have a strong genetic component – and other forms of early-onset SLE ( n = 42). Results The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE ( P < 0.05) and a lower frequency of joint manifestations in familial SLE. Conclusions In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability.
Despite guidelines, poor access to appropriate care for juvenile idiopathic arthritis (JIA) patients remains a global issue. Prompt referral to a pediatric rheumatology (PR) center and effective care ...is known to be critical for changing the natural history of the disease and improving long-term prognosis. This project assesses socio-economic factors of delayed referral to a pediatric rheumatologist (PRst) for JIA patients in France and Switzerland within the Juvenile Inflammatory Rheumatism (JIR) Cohort.
All patients diagnosed with JIA, presenting at one center of the JIRcohort in France or Switzerland with additional data on referral pathway were included. Patient characteristics at first visit to the PR center, dates of visits to healthcare providers during referral, and parent characteristics were extracted from the JIRcohort database.
Two hundred fifty children were included. The overall median time to first PR assessment was 2.4 months 1.3; 6.9 and ranged widely across the JIA subtypes, from 1.4 months 0.6; 3.8 for children with systemic juvenile idiopathic arthritis (sJIA) to 5.3 months 2.0; 19.1 for children with enthesitis-related arthritis (ERA). A diagnosis of ERA and an appointment with an orthopedist during the referral pathway were significantly associated with a longer time before the first PR visit (hazard ratio HR 0.50 95% CI: 0.29; 0.84) and HR 0.68 95% CI: 0.49; 0.93, respectively) in multivariable analysis. Having a mother with a post-graduate educational attainment level was tendentially associated with a shorter time before the first PR visit, (HR 1.32 95% CI: 0.99; 1.78).
Time to first PRst visit was most often short compared to other studies and close to the British recommendations. However, this time remained too long for many patients. We observed no social inequities in access to a PRst, but we show the need to improve effective pathway and access to a PR center for JIA patients.
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