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1.
Artigo em Inglês | MEDLINE | ID: mdl-33420503

RESUMO

OBJECTIVE: To evaluate the impact of anti-Tumour Necrosis Factor-α (anti-TNF) treatment on the occurrence of vasculitic ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). METHODS: A retrospective analysis of DADA2 patients referred from six centres to Great Ormond Street Hospital for Children was conducted. Ischaemic events, vasculitic disease activity, biochemical, immunological, and radiological features were compared, before and after anti-TNF treatment. RESULTS: A total of 31 patients with genetically confirmed DADA2 were included in the study. The median duration of active disease activity prior to anti-TNF treatment was 73 months (inter-quartile range [IQR] 27.5-133.5 months). Twenty seven/31 patients received anti-TNF treatment for a median of 32 months (IQR 12.0-71.5 months). The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months (IQR 1.25-3.63); compared with 0.00 per 100 patient-months (IQR 0.0-0.0) post-treatment (p< 0.0001). Paediatric vasculitis activity score (PVAS) was also significantly reduced: median score of 20/63 (IQR 13.0-25.8/63) pre-treatment vs. 2/63 (IQR 0.0-3.8/63) following anti-TNF treatment (p< 0.0001), with mild livedoid rash being the main persisting feature. Anti-TNF treatment was not effective for severe immunodeficiency or bone marrow failure, which required haematopoietic stem cell transplantation (HSCT). CONCLUSION: Anti-TNF treatment significantly reduced the incidence of ischaemic events and other vasculitic manifestations of DADA2, but was not effective for immunodeficiency or bone marrow failure.

2.
Arthritis Rheumatol ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393715

RESUMO

OBJECTIVES: Vasculopathy is considered central to the pathogenesis of Juvenile dermatomyositis (JDM) and is associated with severe extra-muscular manifestations. We hypothesised that we can non-invasively track the vasculopathy of JDM by examining biomarkers of endothelial injury, subclinical inflammation, hypercoagulability, and vascular arterial stiffness in a UK cohort of children with JDM. METHODS: Circulating endothelial cells (CEC) and microparticles (MP) were identified using immunomagnetic bead extraction, and flow cytometry, respectively. Plasma thrombin generation was determined using a fluorogenic assay. Cytokines/chemokines were measured by electrochemiluminescence. Arterial stiffness was assessed using pulse wave velocity (PWV). Results were expressed as median (interquartile range), and compared with non-parametric analyses (significance at P<0.05). RESULTS: Ninety JDM patients were included; age 10.21 (6.68-13.40) years; disease duration 1.63 (0.28-4.66) years. CEC were higher in all JDM patients at 96 (40-192) cells/ml, compared to 12 (8-24) cells/ml in 79 controls, p<0.0001. Circulating MPs were also significantly higher in active JDM: 204.7 (87.9-412.6) x103 /ml; compared to controls 44.3 (15.0-249.1) x103 /ml, p<0.0001. MP were predominantly of platelet and endothelial origin. Enhanced plasma thrombin generation was demonstrated in active JDM compared to inactive disease (p=0.03); and controls (p=0.001). JDM patients had increased carotid-radial PWV adjusted for age compared to controls (p=0.005). CONCLUSION: We observed increased endothelial injury in active JDM, and increased proinflammatory cytokines. MP profiles reflected distinct disease activity status in JDM, and are markers of vascular pathology, platelet activation and thrombotic propensity. Ongoing long-term vascular injury may result in increased arterial stiffness in JDM.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33181346

RESUMO

BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNFRSF1A gene. Data regarding long-term treatment outcomes is lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in TRAPS patients, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to INSAID classification in group A (pathogenic or likely pathogenic variants), B (VUS or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127/226 patients, 56%), all fulfilled Eurofever criteria and 20/127 patients (16%) developed AA amyloidosis. In group B (78/226 patients, 35%), 40/78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (p<0.02) and higher efficacy rate of on-demand NSAIDs (p<0.02) and colchicine (p<0.001). Group C (21/226 patients, 9%) presented a milder disease (p<0.02) and none fulfilled Eurofever criteria. Anti-interleukin (IL)-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis and seven women with history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in TRAPS patients. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and C, and colchicine may be preferable as first maintenance treatment.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33197261

RESUMO

OBJECTIVES: The objectives of this study were (i) to describe the clinical presentation, treatment and outcome of paediatric inflammatory multisystem syndrome temporally related to Sars-CoV-2 (PIMS-TS) in children; (ii) to propose a framework to guide multidisciplinary team (MDT) management; and (iii) to highlight the role of the paediatric rheumatologist in this context. METHODS: This study involved a retrospective case notes review of patients referred to a single specialist paediatric centre with suspected PIMS-TS, with a focus on clinical presentation, laboratory parameters, treatment, and outcome in the context of an MDT framework. RESULTS: Nineteen children of median age 9.1 years fulfilled the definition of PIMS-TS and were managed within an MDT framework: 5/19 were female; 14/19 were of Black, Asian or minority ethnicity; 9/19 also fulfilled diagnostic criteria for complete or incomplete Kawasaki disease (KD). Severe systemic inflammation, shock, and abdominal pain were ubiquitous. Treatment was stratified within an MDT framework and included CSs in all; i.v. immunoglobulin in all; anakinra in 4/19; infliximab in 1/19; and antiviral (aciclovir) in 4/19. CONCLUSIONS: We observed significant diagnostic equipoise using a current definition of PIMS-TS, overlapping with KD. Outside of clinical trials, an MDT approach is vital. The role of the paediatric rheumatologist is to consider differential diagnoses of hyperinflammation in the young, to advise on empiric immunomodulatory therapy, to set realistic therapeutic targets, to gauge therapeutic success, to oversee timely step-down of immunomodulation, and to contribute to the longer-term MDT follow-up of any late inflammatory sequelae.

6.
Pediatr Rheumatol Online J ; 18(1): 72, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917212

RESUMO

BACKGROUND: Myhre syndrome is a genetic disorder caused by gain of function mutations in the SMAD Family Member 4 (SMAD4) gene, resulting in progressive, proliferative skin and organ fibrosis. Skin thickening and joint contractures are often the main presenting features of the disease and may be mistaken for juvenile scleroderma. CASE PRESENTATION: We report a case of a 13 year-old female presenting with widespread skin thickening and joint contractures from infancy. She was diagnosed with diffuse cutaneous systemic sclerosis, and treatment with corticosteroids and subcutaneous methotrexate recommended. There was however disease progression prompting genetic testing. This identified a rare heterozygous pathogenic variant c.1499 T > C (p.Ile500Thr) in the SMAD4 gene, suggesting a diagnosis of Myhre syndrome. Securing a molecular diagnosis in this case allowed the cessation of immunosuppression, thus reducing the burden of unnecessary and potentially harmful treatment, and allowing genetic counselling. CONCLUSION: Myhre Syndrome is a rare genetic mimic of scleroderma that should be considered alongside several other monogenic diseases presenting with pathological fibrosis from early in life. We highlight this case to provide an overview of these genetic mimics of scleroderma, and highlight the molecular pathways that can lead to pathological fibrosis. This may provide clues to the pathogenesis of sporadic juvenile scleroderma, and could suggest novel therapeutic targets.

8.
Neurol Genet ; 6(4): e448, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32637631

RESUMO

Objective: To report a series of patients with cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma (CBL) gene and examine the functional role of the identified mutant Cbl protein. We hypothesized that mutated Cbl fails to act as a negative regulator of the RAS-mitogen-activated protein kinases (MAPK) signaling pathway, resulting in enhanced vascular fibroblast proliferation and migration and enhanced angiogenesis and collateral vessel formation. Methods: We performed whole-exome sequencing in 11 separate families referred to Great Ormond Street Hospital, London, with suspected genetic cause for clinical presentation with severe progressive cerebral arteriopathy. Results: We identified heterozygous variants in the CBL gene in 5 affected cases from 3 families. We show that impaired CBL-mediated degradation of cell surface tyrosine kinase receptors and dysregulated intracellular signaling through the RAS-MAPK pathway contribute to the pathogenesis of the observed arteriopathy. Mutated CBL failed to control the angiogenic signal relay of vascular endothelial growth factor receptor 2, leading to prolonged tyrosine kinase signaling, thus driving angiogenesis and collateral vessel formation. Mutant Cbl promoted myofibroblast migration and proliferation contributing to vascular occlusive disease; these effects were abrogated following treatment with a RAF-RAS-MAPK pathway inhibitor. Conclusions: We provide a possible mechanism for the arteriopathy associated with heterozygous CBL variants. Identification of the key role for the RAS-MAPK pathway in CBL-mediated cerebral arteriopathy could facilitate identification of novel or repurposed druggable targets for treating these patients and may also provide therapeutic clues for other cerebral arteriopathies.

10.
Rheumatology (Oxford) ; 59(4): e24-e32, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32096545
12.
J Allergy Clin Immunol ; 145(6): 1664-1672.e10, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31945408

RESUMO

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

13.
Neurology ; 94(5): e474-e480, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31892634

RESUMO

OBJECTIVE: Varicella zoster virus (VZV) can spread anterogradely and infect cerebral arteries causing VZV vasculopathy and arterial ischemic stroke. In this study, we tested the hypothesis that virus-infected cerebrovascular fibroblasts undergo phenotypic changes that promote vascular remodeling and facilitate virus transmission in an in vitro model of VZV vasculopathy. The aims of this project were therefore to examine the changes that virus-infected human brain adventitial vascular fibroblasts (HBVAFs) undergo in an in vitro model of VZV vasculopathy and to identify disease biomarkers relating to VZV-related vasculopathy. METHODS: HBVAFs were infected with VZV, and their ability to migrate, proliferate, transdifferentiate, and interact with endothelial cells was studied with flow cytometry. Microparticles (MPs) released from these cells were isolated and imaged with transmission electron microscopy, and their protein content was analyzed with mass spectrometry. Circulating MP profiles were also studied in children with VZV and non-VZV vasculopathy and compared with controls. RESULTS: VZV-infected HBVAFs transdifferentiated into myofibroblasts with enhanced proliferative and migratory capacity. Interaction of VZV-infected HBVAFs with endothelial cells resulted in endothelial dysfunction. These effects were, in part, mediated by the release of MPs from VZV-infected HBVAFs. These MPs contained VZV virions that could transmit VZV to neighboring cells, highlighting a novel model of VZV cell-to-cell viral dissemination. MPs positive for VZV were significantly higher in children with VZV-related vasculopathy compared to children with non-VZV vasculopathy (p = 0.01) and controls (p = 0.007). CONCLUSIONS: VZV-infected HBVAFs promote vascular remodeling and facilitate virus transmission. These effects were mediated by the release of apoptotic MPs that could transmit VZV infection to neighboring cells through a Trojan horse means of productive viral infection. VZV+ MPs may represent a disease biomarker worthy of further study.


Assuntos
Movimento Celular , Proliferação de Células , Transdiferenciação Celular , Micropartículas Derivadas de Células/virologia , Transtornos Cerebrovasculares/virologia , Fibroblastos/virologia , Miofibroblastos/virologia , Remodelação Vascular , Adolescente , Túnica Adventícia , Micropartículas Derivadas de Células/ultraestrutura , Artérias Cerebrais , Transtornos Cerebrovasculares/fisiopatologia , Criança , Pré-Escolar , Células Endoteliais , Feminino , Fibroblastos/fisiologia , Fibroblastos/ultraestrutura , Herpesvirus Humano 3 , Humanos , Técnicas In Vitro , Masculino , Espectrometria de Massas , Microscopia Eletrônica de Transmissão , Miofibroblastos/fisiologia , Miofibroblastos/ultraestrutura , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/virologia , Cultura de Vírus
15.
Rheumatology (Oxford) ; 59(3): 554-558, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31384939

RESUMO

OBJECTIVES: Hereditary systemic autoinflammatory diseases are rare genetic disorders, which if untreated, can be complicated by AA amyloidosis leading to renal failure and premature death. Our objective was to find a genetic cause in a British family with a dominantly inherited autoinflammatory disease complicated by AA amyloidosis. METHODS: The index patient and his sister underwent comprehensive clinical and laboratory assessment including the next-generation sequencing panel targeting autoinflammatory genes. Subsequently, other relatives underwent clinical evaluation and genetic testing. Screening of the SAA1 gene was performed in all symptomatic cases. RESULTS: The index case and his sister presented with proteinuria due to AA amyloidosis. They have been suffering from episodes of fever accompanied by severe abdominal and chest pain, arthritis and erythema since childhood. Their father died aged 52 years from complications following a cadaveric renal transplantation. The post-mortem examination demonstrated AA amyloidosis. The index case's grandmother, two paternal cousins and two of their children described similar symptoms. All symptomatic individuals had excellent responses to colchicine. Next-generation sequencing analysis identified a single MEFV p.P373L variant in the index case, his sister and subsequently, in symptomatic family members. Sequencing of the SAA1 gene revealed all cases were heterozygous for the SAA1.1 allele. CONCLUSION: Typically FMF is an autosomal recessive disorder; nonetheless rare cases of dominantly inherited disease have previously been described. Here we report a novel MEFV variant p.P373L, causing dominant FMF complicated by AA amyloidosis in four generations of a British family.


Assuntos
Amiloidose/genética , Febre Familiar do Mediterrâneo/genética , Pirina/genética , Adulto , Amiloidose/tratamento farmacológico , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
16.
Life Sci Alliance ; 3(2)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31882397

RESUMO

We identified a consanguineous kindred, of three affected children with severe autoinflammation, resulting in the death of one sibling and allogeneic stem cell transplantation in the other two. All three were homozygous for MEFV p.S208C mutation; however, their phenotype was more severe than previously reported, prompting consideration of an oligogenic autoinflammation model. Further genetic studies revealed homozygous mutations in TRAP1, encoding the mitochondrial/ER resident chaperone protein tumour necrosis factor receptor associated protein 1 (TRAP1). Identification of a fourth, unrelated patient with autoinflammation and compound heterozygous mutation of TRAP1 alone facilitated further functional studies, confirming the importance of this protein as a chaperone of misfolded proteins with loss of function, which may contribute to autoinflammation. Impaired TRAP1 function leads to cellular stress and elevated levels of serum IL-18. This study emphasizes the importance of considering digenic or oligogenic models of disease in particularly severe phenotypes and suggests that autoinflammatory disease might be enhanced by bi-allelic mutations in TRAP1.

17.
Heart ; 106(6): 411-420, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31843876

RESUMO

Kawasaki disease (KD) is an inflammatory disorder of young children, associated with vasculitis of the coronary arteries with subsequent aneurysm formation in up to one-third of untreated patients. Those who develop aneurysms are at life-long risk of coronary thrombosis or the development of stenotic lesions, which may lead to myocardial ischaemia, infarction or death. The incidence of KD is increasing worldwide, and in more economically developed countries, KD is now the most common cause of acquired heart disease in children. However, many clinicians in the UK are unaware of the disorder and its long-term cardiac complications, potentially leading to late diagnosis, delayed treatment and poorer outcomes. Increasing numbers of patients who suffered KD in childhood are transitioning to the care of adult services where there is significantly less awareness and experience of the condition than in paediatric services. The aim of this document is to provide guidance on the long-term management of patients who have vascular complications of KD and guidance on the emergency management of acute coronary complications. Guidance on the management of acute KD is published elsewhere.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Síndrome de Linfonodos Mucocutâneos/complicações , Adulto , Criança , Árvores de Decisões , Humanos , Transição para Assistência do Adulto
18.
Front Immunol ; 10: 2589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781101

RESUMO

Monogenic forms of vasculitis are rare but increasingly recognized. Furthermore, genetic immunodeficiency is increasingly associated with inflammatory immune dysregulatory features, including vasculitis. This case report describes a child of non-consanguineous parents who presented with chronic digital vasculitis early in life, is of short stature, has facial dysmorphia, immunodeficiency (low serum IgA, high serum IgM), recurrent bacterial infections, lymphoproliferation, absence of detectable serum C1q, and low classical complement pathway activity. We identified a previously reported de novo heterozygous pathogenic splice mutation in PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and causing activated PI3Kδ syndrome type II (APDS2). This explained the phenotype, with the exception of digital vasculitis and C1q deficiency, which have never been described in association with APDS2. No mutations were identified in C1QA, B, or C, their promoter regions, or in any other complement component. Functional studies indicated normal monocytic C1q production and release, suggesting that the observed C1q deficiency was caused by peripheral consumption of C1q. Since C1q deficiency has never been associated with APDS2, we assessed C1q levels in two unrelated patients with genetically confirmed APDS2 and confirmed C1q deficiency in those two cases as well. This observation suggests C1q deficiency to be an inherent but previously unrecognized feature of APDS2. We speculate that the consumption of C1q is driven by increased apoptotic bodies derived from immune cellular senescence, combined with elevated IgM production (both inherent features of APDS2). Secondary C1q deficiency in APDS2 may further contribute to immunodeficiency and could also be associated with inflammatory immune dysregulatory phenotypes, such as the digital vasculitis observed in our case.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Complemento C1q/deficiência , Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/metabolismo , Adolescente , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Imunofenotipagem , Fenótipo , Doenças da Imunodeficiência Primária/diagnóstico , Sequenciamento Completo do Genoma
19.
JAMA Netw Open ; 2(10): e1914274, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31664448

RESUMO

Importance: Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective: To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation. Design, Setting, and Participants: Cohort study in which a total of 257 genes associated with monogenic neuroinflammation and/or cerebral vasculopathy, including monogenic noninflammatory diseases mimicking these entities, were selected. A customized enrichment capture array, the neuroinflammation gene panel (NIP), was created. Targeted high-coverage sequencing was applied to DNA samples taken from eligible patients referred to Great Ormond Street Hospital in London, United Kingdom, between January 1, 2017, and January 30, 2019, because of onset of disease early in life, family history, and/or complex neuroinflammatory phenotypes. Main Outcomes and Measures: The main outcome was the percentage of individuals with definitive molecular diagnoses, variant classification, and clinical phenotyping of patients with pathogenic variants identified using the NIP panel. The NIP panel was initially validated in 16 patients with known genetic diagnoses. Results: The NIP was both sensitive (95%) and specific (100%) for detection of known mutations, including gene deletions, copy number variants, small insertions and deletions, and somatic mosaicism with allele fraction as low as 3%. Prospective testing of 60 patients (30 [50%] male; median [range] age, 9.8 [0.8-20] years) presenting with heterogeneous neuroinflammatory phenotypes revealed at least 1 class 5 (clearly pathogenic) variant in 9 of 60 patients (15%); 18 of 60 patients (30%) had at least 1 class 4 (likely pathogenic) variant. Overall, a definitive molecular diagnosis was established in 12 of 60 patients (20%). Conclusions and Relevance: The NIP was associated with molecular diagnosis in this cohort and complemented routine laboratory and radiological workup of patients with neuroinflammation. Unexpected genotype-phenotype associations in patients with pathogenic variants deviating from the classic phenotype were identified. Obtaining an accurate molecular diagnosis in a timely fashion informed patient management, including successful targeted treatment in some instances and early institution of hematopoietic stem cell transplantation in others.


Assuntos
Encefalopatias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Inflamação/genética , Adolescente , Criança , Pré-Escolar , Genótipo , Humanos , Lactente , Londres , Técnicas de Diagnóstico Molecular , Mutação , Fenótipo , Sensibilidade e Especificidade , Adulto Jovem
20.
Rheumatol Adv Pract ; 3(1): rkz004, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31431992

RESUMO

Objective: The aim was to carry out a retrospective review of the efficacy and safety of anakinra in paediatric patients with undifferentiated autoinflammatory disease (uAID). Methods: We carried out a retrospective study of children with uAID at a single quaternary centre. The clinical efficacy of anakinra was evaluated using physician global assessment (PGA) and serological response assessed by levels of serum amyloid A and CRP. Safety was assessed by exploring adverse events, including infection and drug reactions. Results: This study included 22 patients, 64% females and 36% males of median age 7.1 years (range 0.13-14.11 years), with uAID. The median starting dose of anakinra was 2 mg/kg (range 2-6 mg/kg) and the median duration of treatment 19.6 months (range 0.8-100 months). Before anakinra treatment, the median PGA, on a three-point Likert scale, was 2 (range 1-2), which fell to 1 (range 0-2) within 3 months of treatment. Eight of 22 (36%) patients achieved complete clinical and serological remission; 8/22 (36%) achieved a partial response; and 6/22 (28%) had no response to anakinra. Adverse events included death (3/22, 14%) and allogeneic haematopoietic stem cell transplantation (1/22, 5%). There were no new safety signals, and anakinra was well tolerated overall. Conclusion: Retrospectively, 72% of children with uAID responded well to anakinra, with 36% achieving full clinical and serological remission within 3 months. This suggests that empirical trials of IL-1 blockade might be warranted in children with uAID. Clear stopping criteria based on predefined parameters should be considered, because non-responders required alternative therapies, facilitated by a definitive molecular diagnosis where possible.

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