Abstract Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1β release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, β, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFβ anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still’s disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes. (SAIDs activity immunity presentations discovery 40 diagnoses phenotypes needed follows i (i inflammasomopathies inflammasomes IL1β ILβ IL 1β β release ii (ii relopathies NFκB NF κB iii (iii IL18/IL36 IL18IL36 ILIL 18/IL 36 18 IL-18/IL-3 defectinduced defect induced damage skin iv (iv interferonopathies IFNs, IFNs , (IFNs) α ε v (v antiinflammatory anti inflammatory impairmentinduced impairment IL10 10 disruption vi (vi syndrome osteomyelitischronic osteomyelitis Stills Still s others classification agents inhibitors IL1 1 IL- blockers 4 IL18 IL36 IL18/IL3 IL18IL3 18IL 3 IL-18/IL- (IFNs IL3 IL18/IL IL18IL IL-18/IL

Abstract Introduction Seasonal influenza A (H3N2) virus is an important cause of morbidity and mortality in the last 50 years in population that is greater than the impact of H1N1. Data assessing immunogenicity and safety of this virus component in juvenile systemic lupus erythematosus (JSLE) is lacking in the literature. Objective To evaluate short-term immunogenicity and safety of influenza A/Singapore (H3N2) vaccine in JSLE. Methods 24 consecutive JSLE patients and 29 healthy controls (HC) were vaccinated with influenza A/Singapore/ INFIMH-16-0019/2016(H3N2)-like virus. Influenza A (H3N2) seroprotection (SP), seroconversion (SC), geometric mean titers (GMT), factor increase in GMT (FI-GMT) titers were assessed before and 4 weeks post-vaccination. Disease activity, therapies and adverse events (AE) were also evaluated. Results JSLE patients and controls were comparable in current age [14.5 (10.1–18.3) vs. 14 (9–18.4) years, p = 0.448] and female sex [21 (87.5%) vs. 19 (65.5%), p = 0.108]. Before vaccination, JSLE and HC had comparable SP rates [22 (91.7%) vs. 25 (86.2%), p = 0.678] and GMT titers [102.3 (95% CI 75.0–139.4) vs. 109.6 (95% CI 68.2–176.2), p = 0.231]. At D30, JSLE and HC had similar immune response, since no differences were observed in SP [24 (100%) vs. 28 (96.6%), p = 1.000)], SC [4 (16.7%) vs. 9 (31.0%), p = 0.338), GMT [162.3 (132.9–198.3) vs. 208.1 (150.5–287.8), p = 0.143] and factor increase in GMT [1.6 (1.2–2.1) vs. 1.9 (1.4–2.5), p = 0.574]. SLEDAI-2K scores [2 (0–17) vs. 2 (0–17), p = 0.765] and therapies remained stable throughout the study. Further analysis of possible factors influencing vaccine immune response among JSLE patients demonstrated similar GMT between patients with SLEDAI < 4 compared to SLEDAI ≥ 4 ( p = 0.713), as well as between patients with and without current use of prednisone ( p = 0.420), azathioprine ( p = 1.0), mycophenolate mofetil ( p = 0.185), and methotrexate ( p = 0.095). No serious AE were reported in both groups and most of them were asymptomatic (58.3% vs. 44.8%, p = 0.958). Local and systemic AE were alike in both groups ( p > 0.05). Conclusion This is the first study that identified adequate immune protection against H3N2-influenza strain with additional vaccine-induced increment of immune response and an adequate safety profile in JSLE. ( www.clinicaltrials.gov , NCT03540823). H3N2 HN H N (H3N2 5 H1N1 (JSLE literature shortterm short term ASingapore Singapore (HC INFIMH160019/2016H3N2like INFIMH1600192016H3N2like INFIMHHNlike INFIMH 16 0019/2016 like 0019 2016 SP, (SP) SC, (SC) GMT, (GMT) FIGMT FI (FI-GMT postvaccination. postvaccination post vaccination. vaccination post-vaccination activity (AE evaluated 14.5 145 [14. 10.1–18.3 101183 10 1 18 3 (10.1–18.3 vs 9–18.4 9184 (9–18.4 0.448 0448 0 448 21 87.5% 875 87 (87.5% 65.5%, 655 65.5% 65 (65.5%) 0.108. 0108 0.108 . 108 0.108] 22 91.7% 917 91 7 (91.7% 86.2%, 862 86.2% 86 (86.2%) 0.678 0678 678 102.3 1023 102 [102. 95% 95 (95 75.0–139.4 7501394 75 139 1096 109 6 109. 68.2–176.2, 6821762 68.2–176.2 68 176 68.2–176.2) 0.231. 0231 0.231 231 0.231] D30 D 100% 100 (100% 96.6%, 966 96.6% 96 (96.6%) 1.000, 1000 1.000 000 1.000)] [ 16.7% 167 (16.7% 31.0%, 310 31.0% 31 (31.0%) 0.338, 0338 0.338 338 0.338) 162.3 1623 162 [162. 132.9–198.3 13291983 132 198 (132.9–198.3 2081 208 208. 150.5–287.8, 15052878 150.5–287.8 150 287 8 (150.5–287.8) 0.143 0143 143 1.6 [1. 1.2–2.1 1221 (1.2–2.1 1. 1.4–2.5, 1425 1.4–2.5 (1.4–2.5) 0.574. 0574 0.574 574 0.574] SLEDAI2K SLEDAIK 2K K 0–17 017 17 (0–17 0–17, 0.765 0765 765 0.713, 0713 0.713 713 0.713) 0.420, 0420 0.420 420 0.420) 1.0, 1.0 1.0) 0.185, 0185 0.185 185 0.185) 0.095. 0095 0.095 095 0.095) 58.3% 583 58 (58.3 44 44.8% 0.958. 0958 0.958 958 0.958) 0.05. 005 0.05 05 0.05) H3N2influenza HNinfluenza vaccineinduced induced wwwclinicaltrialsgov www clinicaltrials gov NCT03540823. NCT03540823 NCT NCT03540823) H3N (H3N H1N INFIMH160019 2016H3N2like 00192016 0019/201 001 201 (SP (SC (GMT 14. [14 10.1–18. 10118 (10.1–18. 9–18. 918 (9–18. 0.44 044 87.5 (87.5 65.5 (65.5% 010 0.10 91.7 (91.7 86.2 (86.2% 0.67 067 67 102. [102 (9 75.0–139. 750139 13 682176 68.2–176. 023 0.23 23 D3 (100 96.6 (96.6% 1.00 00 1.000) 16.7 (16.7 31.0 (31.0% 033 0.33 33 162. [162 132.9–198. 1329198 (132.9–198. 20 1505287 150.5–287. 15 (150.5–287.8 0.14 014 [1 1.2–2. 122 (1.2–2. 142 1.4–2. (1.4–2.5 057 0.57 57 0–1 01 (0–1 0.76 076 76 071 0.71 71 042 0.42 42 018 0.18 009 0.09 09 58.3 (58. 44.8 0.95 0.0 NCT0354082 INFIMH16001 HNlike 0019201 0019/20 10.1–18 1011 (10.1–18 9–18 (9–18 0.4 04 87. (87. 65. (65.5 0.1 91. (91. 86. (86.2 0.6 06 [10 75.0–139 75013 68217 68.2–176 02 0.2 (10 96. (96.6 16. (16. 31. (31.0 03 0.3 [16 132.9–198 132919 (132.9–198 150528 150.5–287 (150.5–287. 1.2–2 12 (1.2–2 1.4–2 (1.4–2. 0.5 0– (0– 0.7 07 58. (58 44. 0.9 0. NCT035408 INFIMH1600 001920 0019/2 10.1–1 101 (10.1–1 9–1 (9–1 (87 (65. (91 (86. 75.0–13 7501 6821 68.2–17 (1 (96. (16 (31. 132.9–19 13291 (132.9–19 15052 150.5–28 (150.5–287 1.2– (1.2– 1.4– (1.4–2 (0 (5 NCT03540 INFIMH160 00192 0019/ 10.1– (10.1– 9– (9– (8 (65 (86 75.0–1 750 682 68.2–1 (96 (31 132.9–1 1329 (132.9–1 1505 150.5–2 (150.5–28 1.2 (1.2 1.4 (1.4– NCT0354 INFIMH16 10.1 (10.1 (6 75.0– 68.2– (3 132.9– (132.9– 150.5– (150.5–2 (1. (1.4 NCT035 INFIMH1 10. (10. 75.0 68.2 132.9 (132.9 150.5 (150.5– NCT03 75. 68. 132. (132. 150. (150.5 NCT0 (132 (150. (13 (150 (15

Resumo Objetivo: avaliar problemas de saúde mental em enfermeiros pediátricos durante a pandemia causada pelo coronavírus 2019. Método: estudo transversal realizado com enfermeiros pediátricos do Instituto da Criança e do Adolescente, por meio de uma pesquisa online de autoavaliação sobre prática clínica e impacto na saúde mental, durante a pandemia de COVID-19. Foram avaliadas escalas de autoavaliação validadas para ansiedade, depressão e burnout. Resultados: 107/298(36%) enfermeiros responderam, dos quais 90% eram do sexo feminino, a mediana de idade atual era 41(23-64) anos, 68% trabalhavam com adolescentes, 66% trabalhavam na linha de frente. Burnout, ansiedade e depressão moderada/grave ocorreram em 65%, 72% e 74% dos enfermeiros, respectivamente. Falta de protocolo de tratamento padronizado nas enfermarias (27% vs. 10%, p=0,049), depressão moderada/grave (74% vs. 16%, p=0,002) e burnout (82% vs. 58%, p=0,01) foram significativamente maiores em enfermeiros pediátricos com ansiedade, em comparação com enfermeiros sem essa condição. Os enfermeiros pediátricos que trabalhavam com adolescentes apresentaram maior frequência de burnout, quando comparados aos que não trabalhavam com esse grupo (77% vs. 32%, p=0,0001). A análise multivariada revelou que o cumprimento adequado da quarentena aumentou a presença de ansiedade em 4,6 vezes [OR 4.6(IC 1,1-20,2), p=0,04]. Conclusão: a maioria dos enfermeiros pediátricos atuava na linha de frente da COVID-19, em condições precárias, trabalhando com equipe reduzida e enfrentando perdas expressivas de renda. A ansiedade atual foi um tema relevante e o burnout também foi uma condição mental importante para esses profissionais, reforçando a cultura do bom trabalho em equipe, das práticas de colaboração e do cuidado psicológico/psiquiátrico.

Abstract Objective: to assess mental health issues in pediatric nurses during coronavirus pandemic in 2019. Method: cross-sectional study was conducted with pediatric nurses at the Instituto da Criança e do Adolescente based on online self-rated survey about clinical practice and mental health impact during COVID-19 pandemic. Validated self-reported scales for anxiety, depression and burnout were used for assessing these professionals. Results: 107/298 (36%) nurses answered, 90% were female, median age was 41(23-64) years, 68% worked with adolescents, 66% in frontline. Burnout, anxiety and moderate/severe depression occurred in 65%, 72% and 74%, respectively. Lack of standardized treatment protocol for nurses (27%vs.10%, p=0.049), moderate/severe depression (74% vs. 16%, p=0.002) and burnout (82% vs. 58%, p=0.01) were significantly higher in pediatric nurses with anxiety compared to those without. Pediatric nurses that worked with adolescents compared to those that did not showed higher frequency of burnout in the former group (77% vs. 32%, p=0.0001). Multivariable analysis revealed that adequate quarantine adherence increased the presence of anxiety in 4.6 times [OR4.6(CI 1.1-20.2), p=0.04]. Conclusion: most pediatric nurses who had worked in the frontline of COVID-19 were under precarious conditions, working with reduced team, and with an expressive changes in their monthly income. Current anxiety was a relevant issue, burnout was also an important mental condition for these professionals, reinforcing culture of good teamwork, collaboration practices and psychological/psychiatric approach.

Resumen Objetivo: evaluar los problemas de salud mental en enfermeros pediátricos durante la pandemia del coronavirus 2019. Método: estudio transversal realizado con enfermeros pediátricos del Instituto da Criança e do Adolescente mediante una encuesta de autoevaluación en línea sobre la práctica clínica y el impacto en la salud mental durante la pandemia de COVID-19. Se evaluaron escalas de autoevaluación validadas para ansiedad, depresión y burnout. Resultados: respondieron 107/298 (36%) de los enfermeros, de los cuales 90% eran del sexo femenino, la mediana de edad actual fue de 41 (23-64) años, 68% trabajaban con adolescentes, 66% trabajaban en primera línea. Burnout, ansiedad y depresión moderada/grave ocurrieron en 65%, 72% y 74% de los enfermeros, respectivamente. Falta de protocolo de tratamiento estandarizado en las enfermerías (27% vs. 10%, p=0,049), depresión moderada/grave (74% vs. 16%, p=0,002) y burnout (82% vs. 58%, p=0,01) fueron significativamente mayores en enfermeros pediátricos con ansiedad en comparación con enfermeros sin esta condición. Los enfermeros pediátricos que trabajaban con adolescentes presentaron mayor frecuencia de burnout en comparación con los que no trabajaban con adolescentes (77% vs. 32%, p=0,0001). El análisis multivariado reveló que el adecuado cumplimiento de la cuarentena aumentó 4,6 veces la presencia de ansiedad [OR 4.6(IC 1,1-20,2), p=0,04]. Conclusión: La mayoría de los enfermeros pediátricos trabajaban en la primera línea de la COVID-19, en condiciones precarias, trabajando con un equipo reducido y enfrentando importantes pérdidas de ingresos. La ansiedad actual fue un tema relevante y el burnout también fue una condición mental importante para estos profesionales, reforzando la cultura del buen trabajo en equipo, las prácticas colaborativas y la atención psicológica/psiquiátrica.

Adenite cervical >1,5cm é o critério menos frequentemente observado em pacientes com doença de Kawasaki e manifesta-se habitualmente em associação com os demais sintomas da fase aguda. Entretanto, linfadenite febril isolada com intensos sinais flogísticos e flegmão é raramente observada como primeira manifestação da doença de Kawasaki. Assim, relatou-se aqui um caso de uma criança que apresentou linfadenite cervical com celulite adjacente e flegmão mimetizando adenite bacteriana como primeira manifestação da doença de Kawasaki. Paciente previamente hígido, 7 anos, masculino, iniciou quadro de febre, adenite cervical com celulite adjacente e cefaleia intensa, sendo prescrita cefadroxila devido ao diagnóstico clínico de linfadenite bacteriana. Por se manter febril e com piora dos sinais flogísticos, após 1 dia foi internado para receber antibioticoterapia endovenosa (oxacilina e ceftriaxona). Tomografia computadorizada da região cervical mostrou processo infeccioso/inflamatório primário. No quarto dia, apresentou lábios ressecados e descamativos, sendo a oxacilina substituída por clindamicina devido à persistência da febre e sinais flogísticos. No nono dia, iniciou hiperemia ocular não exsudativa. No décimo dia de febre, apresentou exantema em tronco, membros, mãos e pés. Recebeu gamaglobulina endovenosa (2g/kg/dose), evoluiu com resolução dos sintomas e, após 2 dias, recebeu alta hospitalar. No 14odia, apresentou descamação lamelar dos dedos das mãos. Portanto, doença de Kawasaki deve ser considerada no diagnóstico diferencial das linfadenites cervicais febris na infância não responsivas à antibioticoterapia empírica, mesmo que esteja presentes celulite adjacente e flegmão.

Cervical adenitis >1.5cm in diameter is the less frequently observed criteria in patients with Kawasaki disease and it is usually found in association with other symptoms during the acute phase. Moreover, the finding of fever and lymphadenitis with intense local signs of inflammation and phlegmon is rarely seen as the initial manifestation of Kawasaki disease. We report the case of a 7-year-old boy who had cervical lymphadenitis with adjacent cellulitis and phlegmon mimicking bacterial adenitis as the first presentation of Kawasaki disease. The patient had fever, cervical lymphadenitis with adjacent cellulitis, and severe headache. Cefadroxil was prescribed based on the clinical diagnosis of bacterial adenitis. Because he remained febrile and phlogistic signs worsened, after 1 day of hospitalization, antibiotics were administrated intravenously (ceftriaxone and oxacillin). The computed tomography of the neck showed primary infectious/inflammatory process. On the fourth day, the patient had dry and scaly lips, and treatment with oxacillin was replaced by clindamycin because the patient was still febrile. On the ninth day, he presented non-exudative bilateral conjunctival injection. On the tenth day of febrile disease, a rash appeared on his trunk, hands and feet. Patient’s symptoms resolved after intravenous administration of immunoglobulin (2g/kg/dose), and he was discharged 2 days later. On the 14th day, the patient had lamellar desquamation of fingers. Kawasaki disease should be considered as a differential diagnosis in children with febrile cervical lymphadenitis unresponsive to empiric antibiotics even if they have adjacent cellulitis and phlegmon.

A dermatomiosite juvenil (DMJ) é uma doença inflamatória crônica idiopática que afeta principalmente músculos e pele. As lesões cutâneas podem persistir apesar do controle bem-sucedido da miosite. O tacrolimus tópico é um novo agente imunossupressor que tem sido usado no tratamento da dermatite atópica, com poucos relatos de seu uso em miopatias inflamatórias na faixa etária pediátrica. Foram descritos três pacientes com DMJ (dois meninos) com idade atual de 5,7 a 10,6 anos. A terapia inicial administrada para esses pacientes foi: corticosteróide (sistêmico em três e tópico em um), antimalárico em três e metotrexato em dois. Todos apresentavam lesões cutâneas refratárias (eritema malar, eritema difuso e/ou vasculite cutânea) após melhora significativa da fraqueza muscular. Tacrolimus tópico 0,03% foi usado duas vezes ao dia após falha do tratamento prévio. As características das lesões foram avaliadas de acordo com a extensão e a gravidade no início do uso do fármaco e após oito e 16 semanas. Na segunda avaliação (oito semanas), notavelmente um paciente apresentou melhora completa do eritema malar e do eritema difuso em membros e tronco, e dois tiveram melhora parcial do eritema malar e da vasculite cutânea. Na terceira avaliação (16 semanas), dois pacientes tiveram resolução completa das lesões e um apresentava eritema malar persistente e eritema moderado em glúteos e região lombar. No último paciente, a melhora das lesões cutâneas foi alcan-çada apenas após o uso de ciclosporina por 16 semanas. Nenhum deles teve efeitos adversos. Tacrolimus tópico pode ser considerado em pacientes com DMJ e manifestações cutâneas refratárias. Estudos posteriores controlados e randomizados com esse fármaco devem ser realizados nessa doença inflamatória.

Juvenile dermatomyositis (JDM) is a rare idiopathic chronic inflammatory disease that affects mainly muscle and skin. Cutaneous lesions may persist despite successful treatment of myositis. Of note, topical tacrolimus is a new immunosuppressive agent that has been used to treat atopic dermatitis with few reports in pediatric inflammatory myopathies. Three JDM patients (two males) were described, current age from 5.7 to 10.6 years. The initial therapy administered for these patients were: corticosteroid (oral in three and topical in one), antimalarial in three and methotrexate in two. All of them had refractory skin lesions (malar rash, extensive rash and/or cutaneous vasculitis) after significant improvement of muscle weakness. Topical tacrolimus 0.03% was used twice daily after failure of previous treatment. The features of lesions were evaluated according to extension and severity at start of drug and after 8 and 16 weeks. At the second evaluation (8 weeks), remarkably one patient had complete improvement of malar rash and extensive rash in limbs and trunk, and two had partial improvement of malar rash and cutaneous vasculitis. At the third evaluation (16 weeks), two patients had complete resolution of lesions and one had persistent malar rash and moderate lumbar and gluteus rash. In the last patient, the improvement of skin lesions was reached only after 16 weeks of cyclosporine use. None of them had adverse effects. Topical tacrolimus could be considered in JDM patients with refractory cutaneous manifestations. Further randomized controlled trials with this agent should be performed in this inflammatory disease.