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TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.
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Inflamación/enzimología , Proteínas Serina-Treonina Quinasas/deficiencia , Factor de Necrosis Tumoral alfa/farmacología , Células A549 , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis , Autoinmunidad/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Muerte Celular/efectos de los fármacos , Citocinas/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Femenino , Células HEK293 , Homocigoto , Humanos , Quinasa I-kappa B/metabolismo , Inmunofenotipificación , Inflamación/patología , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Mutación con Pérdida de Función/genética , Masculino , Linaje , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo , Receptor Toll-Like 3/metabolismo , Transcriptoma/genética , Vesiculovirus/efectos de los fármacos , Vesiculovirus/fisiologíaRESUMEN
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.
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Resistencia a la Enfermedad/genética , Fiebre Mediterránea Familiar/genética , Peste , Pirina/genética , Selección Genética/genética , Animales , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Resistencia a la Enfermedad/inmunología , Haplotipos , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación , Peste/inmunología , Peste/metabolismo , Pirina/inmunología , Pirina/metabolismo , Turquía , Factores de Virulencia/inmunología , Factores de Virulencia/metabolismo , Yersinia pestisRESUMEN
OBJECTIVES: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. STUDY DESIGN: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. RESULTS: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. CONCLUSIONS: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.
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Edad de Inicio , COVID-19 , Sistema de Registros , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , Niño , COVID-19/epidemiología , COVID-19/mortalidad , COVID-19/complicaciones , Preescolar , Femenino , Masculino , Lactante , Adolescente , Estudios Retrospectivos , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Europa (Continente)/epidemiología , Recién NacidoRESUMEN
OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by febrile polyserositis attacks. Menstruation could be a trigger for attacks. We aimed to analyze the features of adolescent FMF patients with menstruation-associated attacks and propose a management algorithm. METHODS: All female FMF patients who had menarche and visited the Pediatric Rheumatology Unit between January-December 2022, were included into this study. Demographics, general characteristics, and the features of menstrual cycle and FMF attacks were noted. RESULTS: A total of 151 female FMF patients were included. Thirty-five (23.2%) had menstruation-associated attacks. Fever and arthritis were less frequent during the menstruation-associated attacks than the attacks not associated with menstruation in these patients (65.7% vs 88.6%, p= 0.01 and 2.9% vs 20%, p= 0.04; respectively). Patients with menstruation-associated FMF attacks were younger at symptom onset and diagnosis (2.5 vs 5 years, p= 0.004 and 4 vs 7 years, p= 0.01; respectively), had a higher rate of dysmenorrhea (74.3% vs 38.8%, p< 0.001, respectively) and higher pre- and post-menarche attack frequency (4 vs 2 and 10 vs 0, respectively; p< 0.001 for both) than patients whose attacks were not associated with menstruation. The interventions for menstruation-associated attacks included initiating colchicine, increasing the dose of colchicine, switching from coated to compressed colchicine tablets or anti-interleukin 1 drugs, and on-demand non-steroidal anti-inflammatory drugs, on-demand glucocorticoids, and on-demand anakinra. On-demand therapies were beneficial in controlling menstruation-associated attacks. CONCLUSIONS: This is the largest cohort of adolescent FMF patients with menstruation-associated attacks. Severe FMF may cause tendency to this association. On-demand therapies could be preferred in the management.
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OBJECTIVES: The transition of adolescents and young adults (AYAs) from pediatric to adult-oriented healthcare may be affected by many factors, including the personal and cultural settings. We aimed to analyze the transition readiness and the factors affecting the transition success in rheumatology. METHODS: Patients older than 12 years were included in this prospective study. All filled out the Transition Readiness Assessment Questionnaire (TRAQ) 5.0. AYAs were phone-interviewed after their transfer to adult-oriented healthcare. Drug adherence was evaluated with 4-item Morisky Medication Adherence Scale (MMAS-4). AYAs rated their transitional care experience with visual analogue scale (VAS 0-10; 0, the worst; 10, the best). RESULTS: A total of 504 TRAQs were filled out by 406 patients (F/M = 1.5). The total TRAQ score was positively correlated with age and higher in the forms filled out by girls than boys (4.2 vs 4.0, respectively; p= 0.005). The transition was successful for 78 (83.9%) out of 93 patients transferred to adult-oriented healthcare. The VAS for the transition process was lower and the post-transfer MMAS-4 score was worse (8 vs 9, p= 0.030 and 3 vs 4, p= 0.020; respectively) in patients whose transition was not successful when compared with the successfully-transitioned ones. The best-performing TRAQ cut-off value was >4.0 for predicting transfer readiness in rheumatology. CONCLUSION: A TRAQ score of > 4 could be used while deciding about the transfer readiness of AYAs in rheumatology. Improving the AYAs' experience of the transition process and closely monitoring medication adherence during transition are essential for a successful transition.
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OBJECTIVES: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood; the pathogenesis is associated with T cell activation. T cell activation can be counter-balanced by signals generated by inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG-3, and TIM-3. Here, we identify the role of IRs in the pathogenesis of different JIA subtypes. METHODS: In total, we included 67 oligoarticular JIA, 12 IgM-RF negative polyarticular JIA, 17 enthesitis related arthritis, 11 systemic JIA patients and 10 healthy controls. We collected plasma (and synovial fluid) samples from the patients either at the onset or during a flare of their disease. We measured the soluble levels of co-IRs (IL-2Rα, 4-1BB, CD86, TGF-ß1, CTLA-4, PD-L1, PD-1, TIM-3, LAG- 3, Galectin-9) by cytometric bead array kits and their cellular expression (PD-1, CTLA-4, TIM-3, LAG-3) by flow cytometry. We compared the plasma levels and cellular expressions of different co-IRs within different JIA subgroups. RESULTS: The polyarticular-JIA group was different from the three other examined JIA subgroups, having higher levels of plasma sCTLA-4(p< 0.001), sPD-1(p< 0.05), and s4-1BB(p< 0.05) when compared with the other JIA subgroups and healthy controls. We analyzed the cellular surface expression of different co-IRs on the PBMCs of different JIA subtypes. Similar to plasma levels, both the percentage(p< 0.05) and the MFI (mean fluorescence intensity) (p< 0.01) of CTLA4 expression were higher in the poly-JIA subgroup. CONCLUSION: This is the first report studying the expression profile of different co-IRs in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA.
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OBJECTIVES: Colchicine forms the mainstay of treatment in FMF. Approximately 5-10% of FMF patients are colchicine resistant and require anti-IL-1 drugs. We aimed to compare the characteristics of colchicine-resistant and colchicine-responsive patients and to develop a score for predicting colchicine resistance at the time of FMF diagnosis. METHODS: FMF patients (0-18 years) enrolled in the Turkish Paediatric Autoinflammatory Diseases (TURPAID) registry were included. The predictive score for colchicine resistance was developed by using univariate/multivariate regression and receiver operating characteristics analyses. RESULTS: A total of 3445 FMF patients [256 (7.4%) colchicine-resistant and 3189 colchicine-responsive) were included (female:male ratio 1.02; median age at diagnosis 67.4 months). Colchicine-resistant patients had longer, more frequent attacks and were younger at symptom onset and diagnosis (P < 0.05). Fever, erysipelas-like erythema, arthralgia, arthritis, myalgia, abdominal pain, diarrhoea, chest pain, comorbidities, parental consanguinity and homozygosity/compound heterozygosity for exon 10 MEFV mutations were significantly more prevalent among colchicine-resistant than colchicine-responsive patients (P < 0.05). Multivariate logistic regression analysis in the training cohort (n = 2684) showed that age at symptom onset, attack frequency, arthritis, chest pain and having two exon 10 mutations were the strongest predictors of colchicine resistance. The score including these items had a sensitivity of 81.3% and a specificity of 49.1%. In the validation cohort (n = 671), its sensitivity was 93.5% and specificity was 53.8%. CONCLUSION: We developed a clinician-friendly and practical predictive score that could help us identify FMF patients with a greater risk of colchicine resistance and tailor disease management individually at the time of diagnosis.
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Artritis , Fiebre Mediterránea Familiar , Humanos , Femenino , Masculino , Niño , Preescolar , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre Mediterránea Familiar/genética , Colchicina/uso terapéutico , Dolor en el Pecho , Sistema de Registros , Síndrome , PirinaRESUMEN
OBJECTIVE: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice. METHODS: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure. RESULTS: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS. CONCLUSION: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.
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OBJECTIVES: To investigate the severe haematological involvement in children with SLE and assess its clinical associations, treatments, outcome and damage accrual. METHODS: The medical charts of children with SLE in whom haematological involvement was observed were reviewed. Severe haematological indices were defined as autoimmune haemolytic anaemia with a haemoglobin concentration < 8 g/dL, thrombocyte count < 30 000/µL, and neutrophil count < 500/µL. RESULTS: Among the 224 patients included, 102 (45.5%) displayed severe indices, predominantly at the initial involvement, and most frequently as severe anaemia in 54 (24.1%) and severe thrombocytopenia in 45 (20.1%). Disease activity did not differ according to the presence of severe disease indices. In addition, the presence of severe indices at initial involvement did not affect the damage accrual. However, a higher rate of damage (51.1% vs. 29.9%, p = 0.002) and steroid-induced damage (28.9% vs. 8.2%, p < 0.001) was evident in patients with flares of the haematological system. Regression analysis revealed that rituximab treatment during the initial episode (OR:4.5, p = 0.006) and the presence of anticardiolipin antibodies (OR:2.3, p = 0.014) significantly increases the odds for haematological system flare. However, severe indices at initial involvement did not increase the odds of a haematological flare. CONCLUSION: Severe haematological indices at onset are common but not related with disease outcomes. Prevention of flares is important to improve outcomes, and a more rigorous maintenance strategy would benefit most to children who display haematological indices refractory to conventional immunosuppressants and those with anti-cardiolipin antibodies.
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OBJECTIVES: The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS). METHODS: Demographic, clinical, and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen pediatric rheumatology centers across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment. RESULTS: One hundred and sixty-two patients were included in the study. 45 of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72-232) vs 199 (130-371) 109/l], ferritin level on admission [1107 (676-2050) vs 2863 (1193-9562) ng/ml], C-reactive protein level [15.4 (2.9-56) vs 90 (32-160) mg/l], erythrocyte sedimentation rate [13 (3-36) vs 43.5 (13-77) mm/h] and fever duration [5 (4-7.5) vs 10 (7-14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals. CONCLUSION: Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met.
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OBJECTIVE: We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients. METHODS: Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing. RESULTS: The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [c.320+4_320+7del and G188 A (c.563 G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [G109 R (c.325 G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [L809 F (c.2425 C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147 W (c.441 C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy. CONCLUSION: Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations.
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Edad de Inicio , Secuenciación del Exoma , Lupus Eritematoso Sistémico , Mutación , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/diagnóstico , Femenino , Masculino , Niño , Preescolar , Predisposición Genética a la Enfermedad , Endodesoxirribonucleasas/genética , Homocigoto , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Helicasa Inducida por Interferón IFIH1RESUMEN
BACKGROUND: Drug-induced lupus erythematosus (DILE) is the development of lupus-like syndrome following a drug exposure. DILE has been reported less frequently among children than adults. METHODS: In this study, we present four children with DILE and similar published cases through a systematic literature review. RESULTS: We report four children (three girls and one boy) who developed DILE associated with the use of topiramate, doxycycline, etanercept, and ethosuximide. Three of them were positive for anti-histone antibodies. In all patients, the drug was discontinued and symptoms resolved completely. The literature review revealed 48 articles describing 61 children with DILE. In the evaluation of 65 patients (our 4 patients and 61 patients from the literature), the most frequently reported drugs associated with DILE were ethosuximide (n = 13) and minocycline (n = 12). Fever (n = 33), arthralgia (n = 31), rash (n = 30), and arthritis (n = 29) were the most common clinical manifestations. Antinuclear antibody (ANA) was positive in 93.5% of patients and anti-histone antibodies were detected in 72.2% of the patients. As for treatment, the responsible drug was discontinued in all patients, and corticosteroids were initiated in 53.3%. Improvement was achieved in 92.0% of patients. CONCLUSION: For children presenting with SLE features, proper drug history is crucial since DILE may be more frequent than anticipated. An association of the relevant drug with the symptoms, and resolution of symptoms on drug withdrawal provides evidence for the diagnosis of DILE.
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Lupus Eritematoso Sistémico , Humanos , Femenino , Masculino , Niño , Lupus Eritematoso Sistémico/inducido químicamente , Lupus Eritematoso Sistémico/tratamiento farmacológico , Topiramato/efectos adversos , Doxiciclina/efectos adversos , Etosuximida/efectos adversos , Adolescente , Etanercept/efectos adversos , Minociclina/efectos adversos , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , PreescolarRESUMEN
OBJECTIVE: The aim of this study was to characterize childhood-onset systemic lupus erythematosus (SLE) in two large cohorts from Turkey and the United States. METHODS: Patients diagnosed with childhood-onset SLE who fulfilled the 1997 American College of Rheumatology classification criteria for SLE from four reference centers in Turkey and the University of Pittsburgh School of Medicine in the United States were included in this study. A comparative analysis was conducted to evaluate the similarities and differences in clinical and laboratory features, damage accrual, and treatment experiences between the two populations. RESULTS: A total of 174 patients with childhood-onset SLE were included in this study (108 patients from Turkey and 66 patients from the United States). The female-to-male ratio was similar between the two cohorts (â¼3:1, p = .73). The median age at diagnosis was 11.67 years (2.19-17.93) in the Turkish cohort and 13.68 years (2.74-17.93) in the U.S. cohort (p < .001). Photosensitivity (45.4% and 21.2%; p = .007) and renal involvement (41.7% and 36.4%; p = .045) were higher in the Turkish cohort. Anti-Ro/SSA (34.8% and 15.7%; p < .001), anti-Sm (59.1% and 19.4%; p < .001), and anti-RNP (47.0% and 14.8%; p < .001) positivity was more frequent in the U.S. cohort. Current use of rituximab (37.9% and 1.9%; p < .001) and belimumab (19.7% and 0%; p < .001) was more prevalent in the U.S. cohort, while the use of cyclophosphamide (often according to the low dose Euro-Lupus protocol) throughout the disease course (24.1% and 4.5%; p < .001) was more frequent in the Turkish cohort. SLICC/ACR Damage Index scores were not different between the two cohorts. CONCLUSION: This study provides detailed clinical and laboratory features of childhood-onset SLE in two independent and geographically divergent cohorts. Our findings suggest an earlier age of disease onset and a higher prevalence of kidney involvement in Turkish patients. Differences in treatment approaches were also noted. However, damage accrual related to SLE does not appear to be different between the two patient populations.
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OBJECTIVE: In this study, we aimed to evaluate the characteristics of pediatric rhupus patients including all the related series in the literature. METHODS: Thirty pediatric patients with rhupus syndrome from 12 different centers in Turkey were included in this study. The literature was also reviewed for pediatric patients with rhupus syndrome. RESULTS: The most prominent phenotype of these 30 patients was juvenile idiopathic arthritis (JIA) (60%) at the disease onset and SLE (73.3%) at the last visit. Major SLE-related organ involvements were skin (80%), hematological system (53.3%), and kidney (23.3%). Arthritis was polyarticular (73.3%), asymmetric (66.7%), and erosive (53.3%) in most patients. Hydroxychloroquine (100%), glucocorticoids (86.7%), and mycophenolate mofetil (46.7%) were mostly used for SLE, while glucocorticoids (76.6%), methotrexate (73.3%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (57.6%) were mainly preferred for JIA. Our literature search revealed 20 pediatric patients with rhupus syndrome (75% were RF positive). The most prominent phenotype was JIA (91.7%) at the disease onset and SLE (63.6%) at the last visit. Major SLE-related organ involvements were skin (66.7%), hematological system (58.3%), and kidney (58.3%). Arthritis was polyarticular (77.8%), asymmetric (63.6%), and erosive (83.3%) in most patients. Glucocorticoid (100%), hydroxychloroquine (76.9%), and azathioprine (46.2%) were mostly used for SLE, while methotrexate (76.9%) and NSAIDs (46.2%) were mainly preferred for the JIA phenotype. CONCLUSION: Our study is the largest cohort in the literature evaluating pediatric rhupus cases. Most of the pediatric patients had polyarticular, asymmetric, and erosive arthritis, as well as organ involvements associated with SLE, including the skin, hematological system, and kidney.
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Artritis Juvenil , Artritis Reumatoide , Lupus Eritematoso Sistémico , Humanos , Niño , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Estudios Retrospectivos , Metotrexato/uso terapéutico , Artritis Reumatoide/complicaciones , Artritis Juvenil/complicaciones , Artritis Juvenil/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Estudios Multicéntricos como AsuntoRESUMEN
OBJECTIVE: To present MRI distribution of active osteitis in a single tertiary referral center cohort of patients with chronic nonbacterial osteomyelitis (CNO). METHODS: Two musculoskeletal radiologists retrospectively reviewed MRI examinations of all patients with a final clinical diagnosis of CNO over 15 years. Sites of active osteitis at any time during the course of disease were divided into seven groups: (A) mandible, sternum, clavicles, or scapulas; (B) upper extremities; (C) subchondral sacrum and ilium immediately subjacent to sacroiliac joints (active osteitis denoting "active sacroiliitis" here); (D) pelvis and proximal 1/3 of femurs (excluding group C); (E) bones surrounding knees including distal 2/3 of femurs and 1/2 of proximal tibias and fibulas; (F) distal legs (including distal 1/2 of tibias and fibulas), ankles, or feet; (G) spine (excluding group C). Temporal changes of lesions in response to treatment (or other treatment-related changes such as pamidronate lines) were not within the scope of the study. RESULTS: Among 97 CNO patients (53 males [55%], 44 females; age at onset, mean ± SD, 8.5 ± 3.2 years; age at diagnosis, 10.3 ± 3.3 years), whole-body (WB) MRI was performed in 92%, mostly following an initial targeted MRI (94%). A total of 557 (346 targeted and 211 WB) MRIs were analyzed. Biopsy was obtained in 39 patients (40%), all consistent with CNO or featuring supporting findings. The most common locations for active osteitis were groups D (78%; 95% CI 69â85%) and C (72%; 95% CI 62â80%). CONCLUSION: Pelvis and hips were preferentially involved in this cohort of CNO patients along with a marked presence of active sacroiliitis. CLINICAL RELEVANCE STATEMENT: When suggestive findings of CNO are identified elsewhere in the body, the next targeted site of MRI should be the pelvis (entirely including sacroiliac joints) and hips, if whole-body MRI is not available or feasible. KEY POINTS: ⢠Heavy reliance on MRI for diagnosis of CNO underscores the importance of suggestive distribution patterns. ⢠Pelvis and hips are the most common (78%) sites of CNO involvement along with active sacroiliitis (72%). ⢠Pelvis including sacroiliac joints and hips should be targeted on MRI when CNO is suspected.
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Imagen por Resonancia Magnética , Osteomielitis , Sacroileítis , Centros de Atención Terciaria , Humanos , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Osteomielitis/diagnóstico por imagen , Estudios Retrospectivos , Sacroileítis/diagnóstico por imagen , Adolescente , Adulto , Niño , Pelvis/diagnóstico por imagen , Adulto Joven , Enfermedad Crónica , Preescolar , Persona de Mediana EdadRESUMEN
OBJECTIVES: Biological drugs are one of the most effective treatment methods for systemic juvenile idiopathic arthritis (SJIA) and can significantly prevent morbidity and mortality. This study aimed to evaluate the efficacy and safety of biologics in patients with SJIA and provide real-life data that might help improve the outcomes. METHODS: TURSIS was a retrospective multicentre study carried out in patients with SJIA for whom a biological treatment had been initiated between 1st March 2013 and 30th December 2018. Data include patients' characteristics, laboratory-clinical results, outcomes, and safety-related variables. The 24-month follow-up data of the patients and the efficacy and safety of biological drugs were evaluated. RESULTS: 147 patients were enrolled. The clinical course of the disease was as follows; it was monocyclic in 38.1%, polycyclic in 49%, and persistent in 12.9% of patients. First-choice biologics were interleukin (IL)-1 blockers in the majority of patients (56.5%), followed by the anti-IL-6 (25.2%) and anti-TNF-alpha drugs (18.4%). Anakinra was the most preferred biologic agent in patients with macrophage activation syndrome (MAS), and tocilizumab was used more frequently in patients with persistent type (p=0.000 and p=0.003). The most frequent switch rate was seen in patients receiving anakinra (n=40/68, 58.8%), and it was most frequently switched to canakinumab (n=32/40, 80%). Better physician's global assessment scores were achieved in patients treated with anakinra in Month 3, compared to other treatments (p=0.04). CONCLUSIONS: The results of our study support the efficacy of biological drugs in particular anti-IL-1 and anti-IL-6 drugs, in the treatment of SJIA. These treatments resulted in improvement in activity of disease and provide a considerable decrease in the frequency of MAS.
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Artritis Juvenil , Productos Biológicos , Síndrome de Activación Macrofágica , Humanos , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Turquía , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Interleucina-1 , Productos Biológicos/efectos adversos , Síndrome de Activación Macrofágica/inducido químicamenteRESUMEN
BACKGROUND: Data on the characteristics of acute kidney injury (AKI) in pediatric COVID-19 and MIS-C are limited. We aimed to define the frequency, associated factors and early outcome of AKI in moderate, severe or critical COVID-19 and MIS-C; and to present a tertiary referral center experience from Türkiye. METHODS: Hospitalized patients ≤ 18 years of age with confirmed COVID-19 or MIS-C at Ihsan Dogramaci Children's Hospital, Hacettepe University, between March 2020-December 2021 were enrolled. The characteristics of AKI in the COVID-19 group were investigated in moderate, severe and critically ill patients; patients with mild COVID-19 were excluded. RESULTS: The median (Q1-Q3) age in the COVID-19 (n = 66) and MIS-C (n = 111) groups was 10.7 years (3.9-15.2) and 8.7 years (4.5-12.7), respectively. The frequency of AKI was 22.7% (15/66) in COVID-19 and 15.3% (17/111) in MIS-C; all MIS-C patients with AKI and 73.3% (11/15) of COVID-19 patients with AKI had AKI at the time of admission. Multivariate analyses revealed need for vasoactive/inotropic agents [Odds ratio (OR) 19.233, p = 0.002] and presence of vomiting and/or diarrhea (OR 4.465, p = 0.036) as independent risk factors of AKI in COVID-19 patients; and need for vasoactive/inotropic agents (OR 22.542, p = 0.020), procalcitonin and ferritin levels as independent risk factors of AKI in the MIS-C group. Age was correlated with lymphocyte count (r = -0.513, p < 0.001) and troponin level (r = 0.518, p < 0.001) in MIS-C patients. Length of hospital stay was significantly longer in both groups with AKI, compared to those without AKI. Mortality was 9.1% in the COVID-19 group; and was associated with AKI (p = 0.021). There was no mortality in MIS-C patients. AKI recovery at discharge was 63.6% in COVID-19 survivors and 100% in MIS-C patients. CONCLUSIONS: Independent risk factors for AKI were need for vasoactive/inotropic agents and vomiting/diarrhea in moderate, severe or critical COVID-19 patients; and need for vasoactive/inotropic agents and severe inflammation in MIS-C patients. Our findings suggest that inflammation and cardiac dysfunction are associated with AKI in MIS-C patients; and the association with age in this group merits further studies in larger groups. Early outcome is favorable; long-term follow-up for kidney functions is needed.
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Lesión Renal Aguda , COVID-19 , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , Niño , COVID-19/complicaciones , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Inflamación , Derivación y Consulta , Diarrea/complicaciones , Vómitos , Estudios RetrospectivosRESUMEN
BACKGROUND: The aim of this study was to reveal the relationship between the health literacy (HL) levels of children with juvenile idiopathic arthritis (JIA) and their parents, and the general health status and physical performance of the children. METHODS: This study included 79 children aged 9-18 years with a diagnosis of JIA and one of their parents. HL levels were evaluated with the Turkish version of the Health Literacy for School-Aged Children and Turkish Health Literacy-32 (THL-32) for children and Adult Health Literacy Scale (AHLS) for their parents. The Childhood Health Assessment Questionnaire (CHAQ), 6-minute walk test (6-MWT), 10-meter walking test (10-MWT) and 10-stair climbing test (10-SCT) was used to evaluate the children. Juvenile Arthritis Biopsychosocial Questionnaire (JAB-Q) was used to assess the children's and parents' psychosocial status and perception of health. RESULTS: HL levels of patients with JIA were 16.5% low HL, %55.7 moderate HL and 27.8% high HL. According to THL-32 scale score, HL level of parents were as follows: inadequate, 3.8%; problematic, 22.8%; sufficient, 34.2%; and excellent, 39.2%. Children's HL levels increase positively as they get older, and no significant relationship was found with other parameters. The AHLS, CHAQ and JAB-Q scores were better in the group with higher education levels of the parents. No statistically significant association was found between the HL of the children and that of the parents. CONCLUSION: In our study, it was found that the high education levels of the parents positively affected the quality of life and physical condition of their children and parental HL levels. In addition, it was shown that the HL levels of children with JIA were not statistically related to other parameters. PATIENT OR PUBLIC CONTRIBUTION: Children diagnosed with JIA and one of their parents actively participated in the study. Feedback from children and families provided important information about obtaining and using HL information before and during the study. The importance of therapy programs and information focusing on the patient and their family, as well as the inter-multidisciplinary approach, in combating a chronic disease at an early age was reinforced by the feedback received from patients and their families.
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Artritis Juvenil , Alfabetización en Salud , Estado de Salud , Padres , Humanos , Artritis Juvenil/psicología , Femenino , Masculino , Niño , Adolescente , Padres/psicología , Encuestas y Cuestionarios , Turquía , Calidad de VidaRESUMEN
Cytokine storm syndromes (CSS) include different entities such as macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis (HLH), and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. An effective management strategy is critical in CSS. While biologics have become an essential part of CSS treatment, hematopoietic stem cell transplantation (HSCT) has changed the fate of primary HLH patients. This chapter will focus on the available alternative immunomodulatory therapies in CSS, which include corticosteroids, cyclosporine A, intravenous immunoglobulin, interleukin 18 binding protein, therapeutic plasmapheresis, HSCT, and mesenchymal stromal cell-based therapies.
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COVID-19 , Síndrome de Liberación de Citoquinas , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/terapia , COVID-19/inmunología , COVID-19/terapia , COVID-19/complicaciones , Trasplante de Células Madre Hematopoyéticas , SARS-CoV-2/inmunología , Linfohistiocitosis Hemofagocítica/terapia , Linfohistiocitosis Hemofagocítica/inmunología , Plasmaféresis/métodos , Agentes Inmunomoduladores/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Trasplante de Células Madre Mesenquimatosas/métodos , Ciclosporina/uso terapéutico , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/terapiaRESUMEN
AIMS: To examine physical functions, activity, and participation level, and associated factors with participation in children with juvenile idiopathic arthritis (JIA) across the International Classification of Functioning Disability and Health-Children and Youth. METHODS: 49 children (Girl/Boy:28/21) aged between 7 and 18 years (Mean: 13.4 ± 3.3) were included. To evaluate body structure/functioning; pain, fatigue, disease activity, and motor functions were assessed. Childhood Health Assessment Questionnaire and Juvenile Arthritis Biopsychosocial and Clinical Questionnaire were used to determine activity level. Child and Adolescent Scale of Participation was used to assess participation. RESULTS: Mild level of pain (2.0 ± 2.3), disease activity (2.0 ± 2.3), and fatigue (4.1 ± 4.0) were recorded. Decrease in motor functions was determined in 75% of children, while 61% of whom had activity-related disability. There was mild to moderate participation restrictions, and participation was significantly associated with age (r = -0.29), pain severity (r = -0.31), disease activity (r = -0.39), motor functions (r = 0.33), and activity level (r = -0.43), (p Ë 0.05). CONCLUSIONS: Majority of children with JIA have deteriorations in physical functions, activity, and participation. Age, pain, disease activity, motor functions and activity level were associated with participation level. Children with JIA should be regularly evaluated multi-directional and they should be referred to rehabilitation programs to increase functionality and participation.