Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: two rare sides of the same devastating coin.

Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

The state of the art in therapeutic administration of botulinum toxin in children with cerebral palsy: an integrative review.

OBJECTIVE: To describe the current state of the art in the therapeutic administration of botulinum toxin with indications, efficacy, and safety profile for children and adolescents with cerebral palsy. DATA SOURCE: An integrative review was conducted. The MEDLINE/PubMed database was searched twice within the last decade using distinct terms, and only studies written in the English language were included. The study population was limited to those aged 0-18 years. Articles that were duplicates or lacked sufficient methodology information were excluded. DATA SYNTHESIS: We found 256 articles, of which 105 were included. Among the included studies, most were conducted in developed countries. Botulinum toxin demonstrated good safety and efficacy in reducing spasticity, particularly when administered by a multidisciplinary rehabilitation team. It is primarily utilized to improve gait and upper limb function, facilitate hygiene care, reduce pain, prevent musculoskeletal deformities, and even decrease sialorrhea in patients without a functional prognosis for walking. CONCLUSIONS: The administration of botulinum toxin is safe and efficacious, especially when combined with a multi-professional rehabilitation team approach, which increases the probability of functional improvement. It can also be beneficial for patients with significant functional impairments to help with daily care tasks, such as hygiene, dressing, and reducing sialorrhea. Pediatricians must be familiar with this treatment and its indications to attend to and refer patients promptly when necessary, and to exploit their neuroplasticity. Further research on this topic is required in developing countries.

The state of the art in therapeutic administration of botulinum toxin in children with cerebral palsy: an integrative review / O estado da arte em aplicação terapêutica de toxina botulínica em crianças com paralisia cerebral: uma revisão integrativa

ABSTRACT Objective: To describe the current state of the art in the therapeutic administration of botulinum toxin with indications, efficacy, and safety profile for children and adolescents with cerebral palsy. Data source: An integrative review was conducted. The MEDLINE/PubMed database was searched twice within the last decade using distinct terms, and only studies written in the English language were included. The study population was limited to those aged 0-18 years. Articles that were duplicates or lacked sufficient methodology information were excluded. Data synthesis: We found 256 articles, of which 105 were included. Among the included studies, most were conducted in developed countries. Botulinum toxin demonstrated good safety and efficacy in reducing spasticity, particularly when administered by a multidisciplinary rehabilitation team. It is primarily utilized to improve gait and upper limb function, facilitate hygiene care, reduce pain, prevent musculoskeletal deformities, and even decrease sialorrhea in patients without a functional prognosis for walking. Conclusions: The administration of botulinum toxin is safe and efficacious, especially when combined with a multi-professional rehabilitation team approach, which increases the probability of functional improvement. It can also be beneficial for patients with significant functional impairments to help with daily care tasks, such as hygiene, dressing, and reducing sialorrhea. Pediatricians must be familiar with this treatment and its indications to attend to and refer patients promptly when necessary, and to exploit their neuroplasticity. Further research on this topic is required in developing countries.

RESUMO Objetivo: Descrever o estado da arte em aplicação terapêutica de toxina botulínica com indicações, eficácia e perfil de segurança em crianças e adolescentes com paralisia cerebral. Fontes de dados: Realizada revisão integrativa através de busca na base de dados MEDLINE/PubMed em dois momentos nos últimos 10 anos, e termos distintos, em inglês, numa população entre 0 e 18 anos de idade. Excluiu-se artigos duplicados ou com informações insuficientes de metodologia. Síntese dos dados: 256 artigos foram encontrados e 105 foram incluídos, sendo a maior parte realizados em países desenvolvidos. A toxina botulínica mostrou boa segurança e efetividade na redução da espasticidade, especialmente administrada por uma equipe de reabilitação multiprofissional, usada principalmente para: melhora da marcha e da função dos membros superiores, facilitação dos cuidados de higiene, analgesia e prevenção de deformidades musculoesqueléticas, além de redução da sialorreia, inclusive em pacientes sem prognóstico funcional de marcha. Conclusões: A aplicação de toxina botulínica foi efetiva e segura, principalmente quando atrelada a uma abordagem por equipe de reabilitação multiprofissional, o que aumenta as chances de melhora funcional. Mostrou-se benéfica também para pacientes com grandes comprometimentos funcionais para facilitar os seus cuidados diários em relação à higiene, colocar e tirar roupas e redução da sialorreia. O pediatra deve estar familiarizado com esse tratamento e suas indicações para atender e direcionar pacientes o mais breve possível quando indicado e aproveitar o máximo de neuroplasticidade. Há necessidade de investimentos em mais pesquisas sobre este tema em países em desenvolvimento.

Tuberculosis among children and adolescents with rheumatic diseases - case series.

BACKGROUND: Rheumatic patients have a higher frequency of tuberculosis(TB) than the general population. This study aimed to describe children and adolescents with TB and rheumatic diseases(RD) who were being treated in a reference center. METHODS: A series of TB cases were investigated in a reference center for childhood TB in Rio de Janeiro, Brazil, from 1995 to 2022. RESULTS: Fifteen patients with underlying RD and TB were included with 8(53%) being female. The mean age at RD diagnosis was 7.10years (SD ± 0,57 years), and the mean age at TB diagnosis was 9.81 years(SD ± 0.88 years). A total of 9 cases of pulmonary TB(PTB) and 6 cases of extrapulmonary TB-pleural(2), joint/osteoarticular(1), cutaneous(1), ocular(1), and peritoneal(1)- were described. The RD observed in the 15 patients included juvenile idiopathic arthritis(9), juvenile systemic lupus erythematosus(3), juvenile dermatomyositis(1), polyarteritis nodosa(1), and pyoderma gangrenosum(1). Among the immunosuppressants/immunobiologics, methotrexate(8) was the most commonly used, followed by corticosteroids(6), etanercept(2), mycophenolate mofetil(1), cyclosporine A(1), adalimumab(1), and tocilizumab(1). The most common symptoms were fever and weight loss, and a predominance of PTB cases was noted. GeneXpert MTB/RIF® was performed in six patients and was detectable in two without rifampicin resistance; Xpert Ultra® was performed in five patients, and traces with indeterminate rifampicin resistance were detected in three. One female patient discontinued treatment, and another passed away. CONCLUSIONS: The case series demonstrated the importance of suspecting and investigating TB in RD affected patients who are using immunosuppressants/ immunobiologics, particularly in countries with high rates of TB such as Brazil.

Multisystem inflammatory syndrome drug treatment in countries with different income profiles: a scoping review.

Objective: The purpose of this study was to map and describe the studies that have investigated therapeutic alternatives for the management of paediatric multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Considering the origin of the studies performed (low-, middle- and high-income countries), a systematic scoping review was conducted with primary studies that reported the use of medications for the treatment of patients with MIS-C. Sources: The searches were performed in MEDLINE, Embase, Lilacs, Epistemonikos, CINAHL, and CENTRAL, in the grey literature (theses and dissertations from CAPES, ProQuest, and PROSPERO) and in clinical trial databases until May 2022. The selection and extraction of studies were performed independently by two reviewers. Summary of the findings: A total of 173 studies were included, most of which were published as case reports or series. No randomized controlled clinical trials (RCTs) were identified. The investigated drugs were immunoglobulins, glucocorticoids, monoclonal antibodies, anticoagulants, and antiplatelet agents. Conclusion: The dosages, when reported, were heterogeneous among the studies. The ethnicity and comorbidity of the participants were poorly reported. Monoclonal antibodies, drugs with higher costs, were mostly described in studies of high-income countries.

Tuberculosis in children and adolescents with rheumatic diseases using biologic agents: an integrative review.

OBJECTIVE: To conduct a bibliographic review on tuberculosis (TB) disease in children and adolescents with rheumatic diseases, being managed with biologic therapy. DATA SOURCE: An integrative review with a search in the U.S. National Library of Medicine and the National Institutes of Health (PubMed) using the following descriptors and Boolean operators: (["tuberculosis"] AND (["children"] OR ["adolescent"]) AND ["rheumatic diseases"] AND (["tumor necrosis factor-alpha"] OR ["etanercept"] OR ["adalimumab"] OR ["infliximab"] OR ["biological drugs"] OR ["rituximab"] OR ["belimumab"] OR ["tocilizumab"] OR ["canakinumab"] OR ["golimumab"] OR ["secukinumab"] OR ["ustekinumab"] OR ["tofacitinib"] OR ["baricitinib"] OR ["anakinra"] OR ["rilonacept"] OR ["abatacept"]), between January 2010 and October 2021. DATA SYNTHESIS: Thirty-seven articles were included, with the total number of 36,198 patients. There were 81 cases of latent tuberculosis infection (LTBI), 80 cases of pulmonary tuberculosis (PTB), and four of extrapulmonary tuberculosis (EPTB). The main rheumatic disease was juvenile idiopathic arthritis. Among LTBI cases, most were diagnosed at screening and none progressed to TB disease during follow-up. Of the TB cases using biologics, most used tumor necrosis factor-alpha inhibitors (anti-TNFα) drugs. There was only one death. CONCLUSIONS: The study revealed a low rate of active TB in pediatric patients using biologic therapy. Screening for LTBI before initiating biologics should be done in all patients, and treatment, in cases of positive screening, plays a critical role in preventing progression to TB disease.

Clinical features, treatment and outcome of pediatric patients with severe cutaneous manifestations in IgA vasculitis: Multicenter international study.

OBJECTIVE: IgA vasculitis (IgAV) (formerly Henoch-Schönlein Purpura, HSP) rarely causes severe skin lesions in children. The purpose of the research was to determine whether severe skin manifestations were associated with a more severe disease course. METHODS: Severe cutaneous manifestations were defined as presence of hemorrhagic vesicles, bullae, ulcerations and/or necroses. Data were collected retrospectively from 12 international tertiary university medical centers. RESULTS: A total of 64 patients with the most severe skin changes in IgAV/HSP and median (Q1, Q3) age of 8.08 (5.08, 11.92) years at the disease onset were compared with 596 IgAV/HSP patients without these manfiestations and median (Q1, Q3) age of 6.33 (4.50, 8.92) years. The patients with severe cutaneous manifestations were older in comparison to other patients with IgAV/HSP (p<0.001), they developed nephritis more frequently (40.6% vs. 20.6%, p = 0.001) with worse outcome of renal disease (p = 0.001). This group of patients also had higher frequencies of severe gastrointestinal complications like hematochezia, massive bleeding and/or intussusception (29.3% vs. 14.8%, p<0.001). d-dimer concentrations were significantly higher in these patients (4.60 mg/L vs. 2.72 mg/L, p = 0.003) and they had more frequent need for treatment with systemic glucocorticoids (84.4% vs. 37.2%, p<0.001) in comparison with the control group. Further multivariate analysis showed that severe cutaneous changes were associated with higher risk of developing nephritis [OR=3.1 (95%CI 1.04-9.21), p = 0.042] and severe gastrointestinal complications [OR=3.65 (95%CI 1.08-12.37), p = 0.038]. CONCLUSION: Patients with IgAV/HSP and severe skin manifestations had a more severe clinical course and more frequently required glucocorticoids compared to classic IgAV/HSP patients.

Tuberculosis in children and adolescents with rheumatic diseases using biologic agents: an integrative review / Tuberculose em crianças e adolescentes com doenças reumáticas em uso de medicamentos biológicos: revisão integrativa

ABSTRACT Objective: To conduct a bibliographic review on tuberculosis (TB) disease in children and adolescents with rheumatic diseases, being managed with biologic therapy. Data source: An integrative review with a search in the U.S. National Library of Medicine and the National Institutes of Health (PubMed) using the following descriptors and Boolean operators: (["tuberculosis"] AND (["children"] OR ["adolescent"]) AND ["rheumatic diseases"] AND (["tumor necrosis factor-alpha"] OR ["etanercept"] OR ["adalimumab"] OR ["infliximab"] OR ["biological drugs"] OR ["rituximab"] OR ["belimumab"] OR ["tocilizumab"] OR ["canakinumab"] OR ["golimumab"] OR ["secukinumab"] OR ["ustekinumab"] OR ["tofacitinib"] OR ["baricitinib"] OR ["anakinra"] OR ["rilonacept"] OR ["abatacept"]), between January 2010 and October 2021. Data synthesis: Thirty-seven articles were included, with the total number of 36,198 patients. There were 81 cases of latent tuberculosis infection (LTBI), 80 cases of pulmonary tuberculosis (PTB), and four of extrapulmonary tuberculosis (EPTB). The main rheumatic disease was juvenile idiopathic arthritis. Among LTBI cases, most were diagnosed at screening and none progressed to TB disease during follow-up. Of the TB cases using biologics, most used tumor necrosis factor-alpha inhibitors (anti-TNFα) drugs. There was only one death. Conclusions: The study revealed a low rate of active TB in pediatric patients using biologic therapy. Screening for LTBI before initiating biologics should be done in all patients, and treatment, in cases of positive screening, plays a critical role in preventing progression to TB disease.

RESUMO Objetivo: Fazer um levantamento bibliográfico referente à tuberculose (TB) em crianças e adolescentes com doenças reumáticas, em uso de imunobiológicos. Fonte de dados: Revisão integrativa com busca na base United States National Library of Medicine (PubMed) utilizando os descritores e operadores booleanos: (["tuberculosis"] AND (["children"] OR ["adolescent"]) AND ["rheumatic diseases"] AND (["tumor necrosis fator-alpha"] OR ["etanercept"] OR ["adalimumab"] OR ["infliximab"] OR ["biological drugs"] OR ["rituximab"] OR ["belimumab"] OR ["tocilizumab"] OR ["canakinumab"] OR ["golimumab"] OR ["secukinumab"] OR ["ustekinumab"] OR ["tofacitinib"] OR ["baricitinib"] OR ["anakinra"] OR ["rilonacept"] OR ["abatacept"]), entre janeiro de 2010 e outubro de 2021. Síntese de dados: Trinta e sete artigos foram incluídos, com o total de 36.198 pacientes. Houve 81 casos de tuberculose latente (ILTB), 80 casos de tuberculose pulmonar (TBP) e quatro casos de tuberculose extrapulmonar (TBEP). A principal doença reumática foi a artrite idiopática juvenil. Entre os casos de ILTB, a maioria foi diagnosticada no rastreio e nenhum evoluiu para a TB. Dos casos de TB em uso de imunobiológicos, a maioria utilizava fármacos antiTNFα. Houve somente um caso de óbito. Conclusões: O estudo demonstrou baixa taxa de TB nos pacientes pediátricos em uso de imunobiológicos. O rastreio para ILTB antes do início da terapia com agentes biológicos deve ser realizado em todos os pacientes, e o tratamento, nos casos de rastreio positivo, é importante para evitar a progressão para TB doença.

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive. METHODS: Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C. RESULTS: We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein-Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients. CONCLUSIONS: This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.

Valuing tonsillitis manifestations in schoolchildren in Rio de Janeiro.

OBJECTIVE: To evaluate the importance attributed to tonsillitis by guardians and their level of knowledge about the disease, correlating their management with their schooling and socioeconomic profiles. METHODS: A quantitative, descriptive and observational cross-sectional study involving students aged 5 to 17 years from state-owned and private schools. A questionnaire was applied on management of tonsillitis and knowledge about rheumatic fever, addressing demographic and socioeconomic data. RESULTS: A total of 323 students were included, predominantly females (61.3%), from state-owned schools (77.1%), with a mean age of 9.7±0.3 years. Among the guardians, 48.6% completed high school. Among the students 75.2% had at least one episode of odynophagia in the previous 12 months. Considering the previous 2 years, 89.8% reported this symptom. There was no collection of bacteriological specimens in 67.8%, and in 83% if taking into account only the last episode, despite the search for medical care in most cases (92.6%). The use of anti-inflammatory drugs was very frequent (43.0% "always" and 42.4% "sometimes"). Among the guardians, 81.7% denied being aware of the relation between rheumatic fever and inappropriate treatment of odynophagia; 85.8% said they wished they had received more information. CONCLUSION: Although it is quite common in schoolchildren, tonsillitis is neglected by many guardians and health professionals, and the ignorance of its relation with rheumatic fever is practically universal, which may contribute to its high prevalence.

Valuing tonsillitis manifestations in schoolchildren in Rio de Janeiro

ABSTRACT Objective: To evaluate the importance attributed to tonsillitis by guardians and their level of knowledge about the disease, correlating their management with their schooling and socioeconomic profiles. Methods: A quantitative, descriptive and observational cross-sectional study involving students aged 5 to 17 years from state-owned and private schools. A questionnaire was applied on management of tonsillitis and knowledge about rheumatic fever, addressing demographic and socioeconomic data. Results: A total of 323 students were included, predominantly females (61.3%), from state-owned schools (77.1%), with a mean age of 9.7±0.3 years. Among the guardians, 48.6% completed high school. Among the students 75.2% had at least one episode of odynophagia in the previous 12 months. Considering the previous 2 years, 89.8% reported this symptom. There was no collection of bacteriological specimens in 67.8%, and in 83% if taking into account only the last episode, despite the search for medical care in most cases (92.6%). The use of anti-inflammatory drugs was very frequent (43.0% "always" and 42.4% "sometimes"). Among the guardians, 81.7% denied being aware of the relation between rheumatic fever and inappropriate treatment of odynophagia; 85.8% said they wished they had received more information. Conclusion: Although it is quite common in schoolchildren, tonsillitis is neglected by many guardians and health professionals, and the ignorance of its relation with rheumatic fever is practically universal, which may contribute to its high prevalence.

Comparison among ACR1997, SLICC and the new EULAR/ACR classification criteria in childhood-onset systemic lupus erythematosus

Abstract Background: To date there are no specific classification criteria for childhood-onset systemic lupus erythematosus (cSLE). This study aims to compare the performance among the American College of Rheumatology (ACR) 1997, the Systemic Lupus International Collaborating Clinics criteria (SLICC) and the new European League Against Rheumatism (EULAR)/ACR criteria, in a cSLE cohort. Methods: We conducted a medical chart review study of cSLE cases and controls with defined rheumatic diseases, both ANA positive, to establish each ACR1997, SLICC and EULAR/ACR criterion fulfilled, at first visit and 1-year-follow-up. Results: Study population included 122 cSLE cases and 89 controls. At first visit, SLICC criteria had higher sensitivity than ACR 1997 (89.3% versus 70.5%, p < 0.001), but similar specificity (80.9% versus 83.2%, p = 0.791), however performance was not statistically different at 1-year-follow-up. SLICC better scored in specificity compared to EULAR/ACR score ≥ 10 at first visit (80.9% versus 67.4%, p = 0.008) and at 1-year (76.4% versus 58.4%, p = 0.001), although sensitivities were similar. EULAR/ACR criteria score ≥ 10 exhibited higher sensitivity than ACR 1997 (87.7% versus 70.5%, p < 0.001) at first visit, but comparable at 1-year, whereas specificity was lower at first visit (67.4% versus 83.2%, p = 0.004) and 1-year (58.4% versus 76.4%, p = 0.002). A EULAR/ACR score ≥ 13 against a score ≥ 10, resulted in higher specificity, positive predictive value, and cut-off point accuracy. Compared to SLICC, a EULAR/ACR score ≥ 13 resulted in lower sensitivity at first visit (76.2% versus 89.3%, p < 0.001) and 1-year (91% versus 97.5%, p = 0.008), but similar specificities at both assessments. When compared to ACR 1997, a EULAR/ACR total score ≥ 13, resulted in no differences in sensitivity and specificity at both observation periods. Conclusions: In this cSLE population, SLICC criteria better scored at first visit and 1-year-follow-up. The adoption of a EULAR/ACR total score ≥ 13 in this study, against the initially proposed ≥10 score, was most appropriate to classify cSLE. Further studies are necessary to address if SLICC criteria might allow fulfillment of cSLE classification earlier in disease course and may be more inclusive of cSLE subjects for clinical studies.

[Indications and adverse events with the use of anti-TNFalpha agents in pediatric rheumatology: experience of a single center]. / Indicacaões e efeitos adversos das drogas anti-TNFalpha em reumatologia pediátrica: experiencia de um unico centro.

OBJECTIVE: To report the efficacy and adverse events with the use of anti-TNFalpha agents in pediatric patients with rheumatic diseases. PATIENTS AND METHODS: Retrospective, observational clinical case series of patients with rheumatic diseases refractory to the conventional treatment. Infliximab and etanercept were the the drugs used. RESULTS: Thirty patients received anti-TNFalpha therapy: Juvenile Idiopathic Arthritis (18), chronic idiopathic anterior uveitis (2), juvenile dermatomyositis (4), Blau syndrome (1), relapsing polychondritis (2), CINCA syndrome (1), and microscopic polyangiitis (1). Twenty (66,6%) patients used infliximab exclusively, 2 (6,6%) etanercept and 8 (26,6%) both drugs. The response with infliximab was good in 9 patients, partial in 12 and poor in 5. Two patients were not evaluated for the short period of treatment. The response with etanercept was good in 7, partial in 2 and poor in 1. The best benefits were observed in JIA patients with polyarticular arthritis, psoriatic arthritis and enthesitis-related arthritis. Adverse effects occurred in 15 patients (50%). Suspension of the treatment due to adverse events occurred in 7. The most frequent infusion reactions with the infliximab were cough and nausea. Infectious complications occurred in 2 patients receiving etanercept and in 7 receiving infliximab (one death due to sepsis). No patients developed tuberculosis. CONCLUSION: Infliximab and etanercept are effective in some subtypes of juvenile idiopathic arthritis and other rheumatic diseases refractory to conventional therapy. Although frequent, adverse events could be controlled most of the time.