Daniela Kaiser

Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

Objectives To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. Methods We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). Results We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. Conclusions Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

International PFAPA syndrome registry: cohort of 214 patients

Address: 1Pediatric Rheumatology of Suisse Romande, Lausanne – Geneva, Switzerland, 2Pediatric Rheumatology, Bordeaux, France, 3Pediatric Rheumatology, Gothenburg, Sweden, 4Pediatric Rheumatology, Haifa, Israel, 5Pediatric Rheumatology, Prag, Czech Republic, 6Pediatric Rheumatology, Kremlin-Bicêtre, France, 7Pediatric Rheumatology, Barcelona, Spain, 8Unit of auto-inflammatory diseases, Montpellier, France, 9Pediatric Rheumatology, Paris, France, 10Pediatric Rheumatology, Lucerne, Switzerland, 11Pediatric Rheumatology, Rome, Italy, 12Pediatric Rheumatology, Lyon, France, 13Pediatric Rheumatology, Leuven, Belgium and 14Pediatric Rheumatology, Genoa, Italy * Corresponding author

Safety of biological agents in paediatric rheumatic diseases: A real-life multicenter retrospective study using the JIRcohorte database

OBJECTIVE To analyse and report the incidence of side effects of biological agents in paediatric patients with inflammatory diseases using of real-life follow-up cohort. METHODS In this international, observational, retrospective, multicentre study of children treated by biological agents and followed in the Juvenile Inflammatory Rheumatism (JIR) cohort (JIRcohorte) network, a Kaplan-Meier method was used to estimate the occurrence of adverse events. A Cox model was constructed to identify independent predictors of adverse events. RESULTS Overall 813 patients totalling 3439 patients-year (PY) of biological agents were included. The main diagnosis was juvenile idiopathic arthritis (84%). A total of 222 patients (27.3%) had 419 adverse events, representing an incidence rate of 12.2 per 100 PY 95% CI [11.0; 13.4]. The overall incidence rate of serious adverse events was 3.9 per 100 PY 95% CI [3.2; 4.6]. Tocilizumab and infliximab were significantly associated with adverse events and canakinumab with serious adverse events. Univariate and multivariable analysis of adverse events and serious adverse events indicated that patients under biological agents with concomitant immunosuppressive drugs (excluding methotrexate) suffered from more of these events. CONCLUSION This study suggests an overall an acceptable safety of biologic agents in children with inflammatory rheumatic diseases treated with biological agents. However, the concomitant prescription of immunosuppressive drugs with biological agents represents a substantial risk of adverse events.

Multicenter retrospective study of biological tolerance in juvenile idiopathic arthritis (jir-cohort)

Ten years after the introduction of biologics in children, we assess the tolerance of these therapies among patients with juvenile idiopathic arthritis (JIA) in pediatric rheumatology centers.

Switch of biotherapies in patients with juvenile idiopathic arthritis: analyses of the JIR cohort data

Biologic treatments have been introduced for Juvenile Idiopathic Arthritis (JIA) treatment in 2000, and have substantially improved the global prognosis of all disease subtypes. However not all patients respond to one biologic and therapeutic effect of one drug may decrease with time.

Prescribed but not approved: biologic agents used without approval in juvenile idiopathic arthritis in Switzerland, France and Belgium

Biologic agents (BA) have profoundly changed the outcome of juvenile idiopathic arthritis (JIA), making inactive disease and clinical remission an achievable goal for treatment. An increasing number of BA has become available in the last 15 years. However, some BA that have been associated to efficacy in some clinical conditions are not approved by legal authority for the use in pediatric population.